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Verdazyl Radicals as Substrates for the Synthesis of Novel Nitrogen-Containing Heterocycles
by
Jeremy Dang
A thesis submitted in conformity with the requirements for the degree of Master of Science
Graduate Department of Chemistry University of Toronto
© Copyright by Jeremy Dang (2010)
ii
Verdazyl Radicals as Substrates for the Synthesis of Novel
Nitrogen-Containing Heterocycles
Jeremy Dang
Master of Science
Graduate Department of Chemistry University of Toronto
2010
Abstract
The emergence of verdazyl radicals as starting materials for organic synthesis is
providing a unique opportunity to create a variety of distinctive heterocyclic scaffolds. These
stable radicals have previously been used as spin probes, polymerization inhibitors, mediators of
living radical polymerizations, and as substrates for molecular-based magnets. However,
verdazyl radicals have never been employed to fulfill an organic synthetic role until recently. In
an effort to pioneer the chemistry behind verdazyl radicals as novel organic substrates, our lab
has been inspired to expand and explore the scope of reactions involving their synthetic utility.
This thesis assesses the synthetic versatility of verdazyl radicals by constructing a library of
structurally complex and diverse verdazyl-derived heterocycles in an approach called diversity-
oriented synthesis. The synthetic versatility was further expanded to the preparation of a
biphenyl-stacked biphenylophane, which exhibited interesting structural and conformational
features as highlighted herein.
iii
Acknowledgments
I would like to express my deepest gratitude to my supervisor Professor Michael K.
Georges for providing me the opportunity to conduct my graduate research in his lab and for his
support during my M.Sc. program. You have taught me valuable chemistry lessons and lab
techniques like running the perfect TLC. I will truly miss your storytelling as your stories were
always a pleasure to listen to. Special thanks go to Dr. Gordon Hamer, who I have acknowledged
as the “NMR Master,” for offering me his time and intelligence in helping me with my
characterizations and VT NMR studies.
I wish to thank the members of the Georges’ lab with whom I have worked with and
befriended: Dr. Julie Lukkarila, Dr. Eric Chen, Matthew Bancerz, and Anna Cumaraswamy. In
the one and a half year that I have been here, all of you have made my experience a valuable and
memorable one. I wish the best for all of you and hope your future endeavors will someday be
realized. I would like to extend my appreciation to Professor Patrick Gunning for being my
second reader and also to the members of the Gunning’s lab: Vijay Shahani, Joel Drewry,
Miriam Avadisian, Brent Page, and Sina Haftchenary. Lastly, I am greatly indebted to my family
who has always provided me the never-ending support to pursue my greatest interests.
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Table of Contents
Abstract................................................................................................................................. ii Acknowledgements............................................................................................................... iii Table of Contents.................................................................................................................. iv List of Schemes..................................................................................................................... vi List of Figures....................................................................................................................... viii List of Tables........................................................................................................................ ix List of Abbreviations............................................................................................................ x 1. Verdazyl Radicals.................................................................................................... 1 1.1 Verdazyl Radicals.................................................................................................... 2 1.2 6-Oxoverdazyl Radicals........................................................................................... 3 1.3 6-Thioxoverdazyl Radicals...................................................................................... 6 1.4 Inorganic Verdazyl Radicals.................................................................................... 6 1.5 Chemistry and Applications of Verdazyl Radicals.................................................. 7 1.6 Summary.................................................................................................................. 9 1.7 References................................................................................................................ 9 2. 1,3-Dipolar Cycloadditions and Azomethine Imines as 1,3-Dipoles................... 12 2.1 1,3-Dipolar Cycloadditions...................................................................................... 12 2.2 Azomethine Imines as 1,3-Dipoles.......................................................................... 16 2.3 Summary.................................................................................................................. 17 2.4 References................................................................................................................ 17 3. Diversity-Oriented Synthesis.......................................................................................... 19 3.1 Target-Oriented Synthesis and Diversity-Oriented Synthesis.................................. 19 3.2 Complexity-Generating Processes (Simple � Complex)........................................ 20 3.3 Diversity-Generating Processes (Similar � Diverse).............................................. 21 3.4 Summary.................................................................................................................. 24 3.5 References................................................................................................................ 25 4. Biphenylophanes – Biphenyl-Based Phanes…........................................................... 26 4.1 Biphenylophanes...................................................................................................... 27 4.2 Biphenyl-Stacked Biphenylophanes........................................................................ 29 4.3 Summary.................................................................................................................. 32 4.4 References................................................................................................................ 32 5. The Emergence of Verdazyl Radicals as Substrates for 1,3-Dipolar
Cycloaddition Reactions.................................................................................................. 34 5.1 Introduction.............................................................................................................. 34 5.2 Development of the 1,3-DC Reaction Initiated with Verdazyl Radicals................. 35 5.3 Summary.................................................................................................................. 39 5.4 References................................................................................................................ 40
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6. Application of Diversity-Oriented Synthesis to Verdazyl Radicals and their Derived Heterocycles...................................................................................... 41
6.1 Introduction and Objective....................................................................................... 41 6.2 Experimental Section............................................................................................... 43 6.3 Results and Discussion............................................................................................. 52 6.4 Concluding Remarks................................................................................................ 56 6.5 Future Work............................................................................................................. 56 6.6 References................................................................................................................ 58 7 Verdazyl Radicals as Precursors to Heteraphanes.................................................. 59 7.1 Introduction and Objective....................................................................................... 59 7.2 Experimental Section............................................................................................... 61 7.3 Results and Discussion............................................................................................. 65 7.4 Concluding Remarks................................................................................................ 72 7.5 Future Work............................................................................................................. 73 7.6 References................................................................................................................ 75 8 Appendix............................................................................................................................. 76
8.1 NMR Spectra for Structure 7.7................................................................................ 76 8.2 Single Crystal X-ray Diffraction Results of 7.7....................................................... 81
vi
List of Schemes
1. Verdazyl Radicals Scheme 1-1. Synthesis of the 1,3,5-triphenylverdazyl radical (1.6)..................................... 2
Scheme 1-2. Synthesis of the 1,5-dimethyl-6-oxoverdazyl radical (1.9).............................. 3 Scheme 1-3. Neugebauer’s synthesis of bis-hydrazide (1.7a,b and 1.18a,b)....................... 3 Scheme 1-4. Hicks’ synthesis of N,N’-dimethylcarbonohydrazide(1.7a)............................. 4 Scheme 1-5. Formation of bis-hydrazide 1.7’ via attack from primary amine..................... 4 Scheme 1-6. Milcent’s synthesis of 1,5-diaryl-6-oxoverdazyl radicals (1.13)..................... 5 Scheme 1-7. Brook’s synthesis of 1,5-diisopropyl-6-oxoverdazyl radical (1.17)................ 5 Scheme 1-8. Hicks’ synthesis of 6-phosphaverdazyl (1.22)................................................. 7 Scheme 1-9. Hicks’ synthesis of 3-phosphaverdazyl (1.24)................................................. 7 Scheme 1-10. Hicks’ synthesis of 6-borataverdazyl radical salt (1.26)................................ 7 Scheme 1-11. Oxidative ring opening of 1,3,5-triphenylverdazyl radical (1.6b)................. 8 Scheme 1-12. Thermolysis of 1,3,5-triphenylverdazyl radical (1.6b).................................. 8 Scheme 1-13. Dimerization of 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical (1.9b).......... 8
2. 1,3-Dipolar Cycloadditions and Azomethine Imines as 1,3-Dipoles Scheme 2-1. General reaction scheme for 1,3-DC reactions................................................ 12
Scheme 2-2. Resonance structures for a generic 1,3-dipole.................................................. 13 Scheme 2-3. Propargyl-allenyl type and allyl type 1,3-dipoles............................................ 13 Scheme 2-4. 1,3-DC reaction of an azomethine imine (2.5) with a dipolarophile (2.6)....... 16 Scheme 2-5. Intramolecular 1,3-DC reaction........................................................................ 17 Scheme 2-6. [3+3] Cycloaddition of an azomethine imine (2.5).......................................... 17
3. Diversity-Oriented Synthesis
Scheme 3-1. Use of tandem reactions to generate structural complexity............................. 21 Scheme 3-2. Diversity-generating process using appendage diversity................................. 22 Scheme 3-3. Diversity-generating process using stereochemical diversity.......................... 23 Scheme 3-4. Reagent-based skeletal diversity-generating process....................................... 23 Scheme 3-5. Substrate-based skeletal diversity-generating process..................................... 24
4. Biphenylophanes – Biphenyl-Based Phanes
Scheme 4-1. Stoddart’s directed synthesis of a cyclophane (4.8) and an analogous biphenylophane (4.11).......................................................................................................... 29 Scheme 4-2. One-pot synthesis of a parallel- (4.19, 4.21) and cross-oriented conformation biphenylophane (4.20, 4.22).......................................................................... 31
5. The Emergence of Verdazyl Radicals as Substrates for 1,3-Dipolar Cycloaddition Reactions
Scheme 5-1. Attempted synthesis of a BSV unimer (5.2).................................................... 35 Scheme 5-2. Proposed mechanism for the formation of the cycloadduct 5.4....................... 36 Scheme 5-3. Rearrangement of pyrazolotetrazinanones (5.16)............................................ 38 Scheme 5-4. Proposed mechanism for pyrazolotriazinones formation................................. 38 Scheme 5-5. Proposed mechanism for triazole formation.................................................... 39
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6. Application of Diversity-Oriented Synthesis to Verdazyl Radicals and their Derived Heterocycles
Scheme 6-1. Planning of DOS to verdazyl radicals and their derived heterocycles............. 42 Scheme 6-2. Synthesized verdazyl-derived compounds....................................................... 53 Scheme 6-3. Proposed pathways for the formation of 6.18.................................................. 55 Scheme 6-4. Appendage diversification towards the synthesis of verdazyl radicals............ 57
7. Verdazyl Radicals as Precursors to Heteraphanes Scheme 7-1. Attempted synthesis of the linear polyverdazyl macrostructure 7.3................ 60 Scheme 7-2. Synthetic route to biphenylophane 7.7............................................................. 67 Scheme 7-3. Proposed mechanism for the transformation from 7.6 to 7.7........................... 68 Scheme 7-4. Decomposition of 7.14 to 7.15......................................................................... 69
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List of Figures
1. Verdazyl Radicals Figure 1-1. Structure of triphenylmethyl radical (1.1) ......................................................... 1
Figure 1-2. The general verdazyl structure with known modifications................................ 1 Figure 1-3. Accurate representation of the 1,3,5-triphenylverdazyl radical (1.6b’) ............ 2 Figure 1-4. 6-Thioxoverdazyl radicals with varying substituent at the N-1 and N-5 positions.......................................................................................................................... 6 Figure 1-5. General structure of an N-alkylated leucoverdazyl (1.27)................................. 7
2. 1,3-Dipolar Cycloadditions and Azomethine Imines as 1,3-Dipoles
Figure 2-1. Examples of propargyl-allenyl type and allyl type 1,3-dipoles......................... 13 Figure 2-2. FMO diagrams................................................................................................... 15
3. Diversity-Oriented Synthesis
Figure 3-1. Retrosynthetic analysis in TOS.......................................................................... 19
4. Biphenylophanes – Biphenyl-Based Phanes Figure 4-1. Structure of a [2.2]metacyclophane (4.1), [2.2]paracyclophane (4.2), and a generic biphenylophane(4.3).............................................................................................. 26 Figure 4-2. Structure of Wedekind’s (4.4) and Adams’ and Kornblum’s (4.5) biphenylophane..................................................................................................................... 28 Figure 4-3. Proposed conformational ring-flipping of a [2.2](3,3’,4,4’)biphenylophane.... 30 Figure 4-4. Structure of dithiabiphenylophane 4.13, 4.14, and 4.15.................................... 30 Figure 4-5. Structure of a face-to-face biphenyl-stacked phane (4.17)................................ 31
5. The Emergence of Verdazyl Radicals as Substrates for 1,3-Dipolar Cycloaddition Reactions
Figure 5-1. Structure of BST unimer (5.1) and BSV unimer (5.2)....................................... 34 6. Application of Diversity-Oriented Synthesis to Verdazyl Radicals and their Derived Heterocycles
Figure 6-1. Structure of a tert-butyl carbamate-containing triazole (6.24)........................... 54 Figure 6-2. Structures of the two lead compounds, 6.28 and 6.29........................................56
7. Verdazyl Radicals as Precursors to Heteraphanes
Figure 7-1. General products formed from the verdazyl radical precursor.......................... 59 Figure 7-2. Retrosynthetic approach to the target biphenylophane 7.7................................ 66 Figure 7-3. 1H NMR spectrum of biphenylophane 7.7 at 296 K.......................................... 70 Figure 7-4. Molecular structure of 7.7 in two different views.............................................. 71 Figure 7-5. Space-filling model of 7.7.................................................................................. 72 Figure 7-6. Structure of 7.16 and 7.17.................................................................................. 74 Figure 7-7. Structure of the polyverdazyl macrostructure 7.18............................................ 74
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List of Tables
4. Biphenylophanes – Biphenyl-Based Phanes Table 4-1. Phane names for some types of bridged aromatic compounds........................... 27
5. The Emergence of Verdazyl Radicals as Substrates for 1,3-Dipolar Cycloaddition Reactions
Table 5-1. Some results from the 1,3-DC reaction between 5.3 with various dipolarophiles........................................................................................................................ 37
x
List of Abbreviations
∆ Heat 1,3-DC 1,3-Dipolar cycloaddition act. Activated Ar General aryl group atm. Atmospheric B: Base BOC tert-Butoxy carbonyl BPO Benzoyl peroxide BQ para-Benzoquinone BST 1-Benzoyloxy-2-phenyl-2-(2’,2’,6’,6’-tetramethyl-1’- piperidinyloxy)ethane BSV 1-Benzoyloxy-2-phenyl-2-(6-oxoverdazyl)ethane d Day(s) DCM Dichloromethane DFT Density functional theory DMF Dimethylformamide DMSO Dimethylsulfoxide DOS Diversity-oriented synthesis ESR Electron spin resonance FMO Frontier molecular orbital h Hour HRMS High resolution mass spectrometry HOMO Highest occupied molecular orbital K Kelvin LRP Living radical polymerization LUMO Lowest unoccupied molecular orbital Me Methyl min. Minute(s) MO Molecular orbital mp Melting point NMR Nuclear magnetic resonance Nu Nucleophile [ox] Oxidation Ph Phenyl iPr iso-Propyl R General functional group rt Room temperature SFRP Stable free radical polymerization TEMPO 2,2,6,6-Tetramethyl-1-piperidinyl-1-oxy THF Tetrahydrofuran TMS Tetramethylsilane TLC Thin layer chromatography TOS Target-oriented synthesis VT Variable temperature
xi
WH Woodward-Hoffmann
1
1. Verdazyl Radicals
Compounds with an unpaired electron(s) are known as radicals and are typically regarded
as highly reactive, transient species as a result of dimerization, hydrogen abstraction, and
disproportionation reactions that are thermodynamically favorable due to low energies of
activation.1 For this reason, it was originally believed that isolating and characterizing radical
species was not feasible. However, this perspective was changed when Gomberg synthesized the
first detectable radical molecule, the triphenylmethyl radical (1.1).2
Figure 1-1. Structure of triphenylmethyl radical (1.1).
The successful synthesis of 1.1 was confirmed by ESR spectroscopy. Unfortunately, isolation of
the species was not possible due to an insufficient half-life of the radical.3 Radicals with these
characteristics are termed persistent radicals while those that can also be isolated, handled, and
stored are called stable radicals.4 Nevertheless, Gomberg’s discovery of a detectable radical
molecule sparked a movement into pursuing other persistent radicals which eventually led to the
emergence of stable radicals. Currently, there are numerous examples of stable radicals1 and
many of them employ bulky substituents for their stability although verdazyls and nitroxides are
two classes of stable radicals that do not rely heavily on steric hindrance for their stabilization.5
Dimerization of these radicals has never been observed and it has been speculated that this
phenomenon is caused by their stability.6
The general structure of a verdazyl radical, 1.2, consists of a 6-membered heterocyclic
ring with four nitrogen atoms at the 1, 2, 4, and 5 positions (Figure 1-2).
Figure 1-2. The general verdazyl structure with known modifications.
The stability of the molecule is attributed to the delocalization of the unshared electron over the
four nitrogen atoms7 and to the steric shielding provided by the R groups at the 1, 3, and 5
2
positions.8a The spin density can be further stabilized via conjugation with any π system the R
groups might contain.9 In this chapter the history, syntheses, chemistry, and applications of
verdazyl radicals will be reviewed.
1.1 Verdazyl Radicals
The first reported verdazyl radical was the 1,3,5-triphenylverdazyl radical, 1.6, which
was unintentionally synthesized by Kuhn and Trischmann in 1963.7a Their objective was to make
an N-alkylformazan, 1.4, by alkylating triphenylformazan 1.3, but the major product isolated was
1.6 (Scheme 1-1). It has been confirmed through detection of 1.4 that the alkylated product 1.4
does form but cyclizes in solution to form the leucoverdazyl 1.5 under thermal or basic
condition. Under an atmosphere of oxygen 1.5 was subsequently oxidized to the verdazyl radical
1.6.6,7b Ensuing studies revealed that the cyclization also occurs in the presence of acid.10
Scheme 1-1. Synthesis of the 1,3,5-triphenylverdazyl radical (1.6).
In an attempt to examine its stability, 1.6b was heated in boiling acetic acid and in
concentrated sodium methoxide solutions to observe any decomposition. However, 1.6b was
stable under both sets of reaction conditions. ESR studies revealed that the stability of 1.6b stems
from the distribution of the unpaired electron across the four nearly equivalent nitrogen atoms of
the backbone.7 Thus, the structure of 1.6b is better represented as 1.6b’ (Figure 1-3).
1.6b’
Figure 1-3. Accurate representation of the 1,3,5-triphenylverdazyl radical (1.6b’).
An X-ray diffraction study of 1.6b showed that the heterocyclic ring of the verdazyl
backbone is bent out of planarity. This is caused by the displacement of both the methylene
carbon C(6) and the benzylic carbon C(3) in the same direction from the plane defined by the
four nitrogen nuclei of the backbone. The magnitude of the displacement is significantly greater
3
for the methylene carbon than the benzylic carbon effectively resulting in an unsymmetrical boat
conformation.8,11 On the other hand, substituting the sp3-hybridized carbon of C(6) with a
carbonyl functionality, where the carbon is sp2-hybridized, induces the backbone to adopt a near
planar conformation.12 Verdazyl radicals with a carbonyl moiety at the 6 position are known as
6-oxoverdazyl radicals.
1.2 6-Oxoverdazyl Radicals
The subclass of 6-oxoverdazyl radicals was first reported by Neugebauer and Fischer in
1980 when they synthesized the 1,5-dimethyl-6-oxoverdazyl radical, 1.9. The two-step synthesis
was initiated by a condensation reaction between N,N’-dimethylcarbonohydrazide, 1.7a, and an
aldehyde, which proceeded through the formation of an imine (Scheme 1-2). Cyclization of the
hydrazone gave the tetrazinanone 1.8, which was subsequently dehydrogenated in a three
electron process by various oxidants to afford 1.9 via the intermediacy of a leucoverdazyl.13
Scheme 1-2. Synthesis of the 1,5-dimethyl-6-oxoverdazyl radical (1.9).
In later years, Neugerbauer published a more efficient and versatile methodology for the
synthesis of 1.7a (Scheme 1-3). In the procedure, four equivalents of methyl- or benzylhydrazine
were reacted with phosgene gas to directly give 1.7a or 1.7b, respectively. In the process, two
equivalents of the hydrazine were consumed to form the hydrazine salt.14
Scheme 1-3. Neugebauer’s synthesis of bis-hydrazide (1.7a,b and 1.18a,b).
Due to the hazard and difficulty associated with handling and storage of phosgene, Hicks
modified Neugebauer’s method by replacing the phosgene with triphosgene (Scheme 1-4).
4
Scheme 1-4. Hicks’ synthesis of N,N’-dimethylcarbonohydrazide(1.7a).
In Hicks’ approach, twelve equivalents of methylhydrazine were reacted with triphosgene to
produce three equivalents of 1.7a and six equivalents of the hydrazine salt. The experimental
yield is reported to be greater than 90 %.15
The R group at the 3 position of 1.9 can be derivatized by employing various aldehydes
for the condensation reaction. As a result, a wide assortment of verdazyl radicals have been
prepared by a number of groups.15,16 Most notably, both Neugebauer and Hicks have contributed
greatly to the library of 1,5-dimethyl-6-oxoverdazyl radicals. Although derivatization at the 3
position can be easily accomplished, the same cannot be said for the 1 and 5 positions. This
limitation originates from an interplay of both electronic and steric factors of the substituted
hydrazine, the precursor to the bis-hydrazide and ultimately the corresponding verdazyl radical.17
In order to achieve a successful synthesis of the verdazyl radical, the lone pair of electrons on the
secondary nitrogen of the substituted hydrazine must perform the nucleophilic attack on the
phosgene (or triphosgene) as opposed to the primary amine. In the case where the opposite
chemoselectivity is observed, bis-hydrazide 1.7’ is formed via the nucleophilic attack by the
primary nitrogen (Scheme 1-5). Since 1.7’ is incapable of forming an imine with an aldehyde,
ring closure does not happen and as a result a tetrazinanone is not formed. This scenario arises in
cases where the secondary amine is weakly nucleophilic, sterically hindered, or a combination of
both.
Scheme 1-5. Formation of bis-hydrazide 1.7’ via attack from primary amine.
Neugebauer has demonstrated that both methyl- and benzylhydrazine can be used to
make the respective bis-hydrazides 1.7a and 1.7b (Scheme 1-4).14 In these hydrazines the
secondary amines are more nucleophilic than the primary ones due to the inductive effect of the
5
methyl and benzyl group. The sterics imposed by the methyl and benzyl groups on the secondary
amine are not influential enough to adversely affect the reactivity of these amines.
In an effort to construct 1,5-diaryl-6-oxoverdazyl radicals, represented by 1.13, Milcent
established a strategy to circumvent the aforementioned chemoselectivity issue (Scheme 1-6).
The problem was resolved by protecting the secondary amine of the arylhydrazine by converting
it to the arylhydrazone 1.10, which underwent a single nucleophilic substitution reaction with
phosgene to produce 1.11. A second addition of arylhydrazine gave 1.12, which was then
oxidized to 1.13.17
Scheme 1-6. Milcent’s synthesis of 1,5-diaryl-6-oxoverdazyl radicals (1.13).
Brook also addressed the chemoselectivity of alkylhydrazine issue in an endeavor to
construct a 1,5-diisopropyl-6-oxoverdazyl radical, 1.17, to improve the stability and solubility of
verdazyl radicals (Scheme 1-7). He utilized a BOC-protected isopropylhydrazine, which reacted
twice with phosgene to form 1.14. The protecting group was removed by acid hydrolysis to give
1.15, which underwent a condensation reaction with an aldehyde to yield 1.16. Subsequent
oxidation of 1.16 provided 1.17. The bulkier isopropyl groups relative to the smaller methyl
groups sterically protects the radical in 1.17, thus reinforcing its stability.18
Scheme 1-7. Brook’s synthesis of 1,5-diisopropyl-6-oxoverdazyl radical (1.17).
6
1.3 6-Thioxoverdazyl Radicals
A few years after disclosing the synthesis of 6-oxoverdazyl radicals, Neugebauer reported
the synthesis of 6-thioxoverdazyl radicals. This subclass of verdazyl radicals contain a thionyl
functionality at the 6 position and X-ray data has shown that the heterocyclic backbone tends to
adopt a flat boat conformation.12 By employing the same method used to make bis-
carbonohydrazides 1.7a and 1.7b the bis-thiocarbonohydrazide 1.18a and 1.18b can be prepared
by using thiophosgene instead of phosgene (Scheme 1-3). Condensation of 1.18a and 1.18b
followed by oxidation resulted in the formation of the 1,5-dimethyl- (1.19a) and 1,5-dibenzyl-6-
thioxoverdazyl (1.19b) radicals, respectively.12,14,16a Utilizing Milcent’s procedure permitted the
synthesis of 1,5-diaryl-6-thioxoverdazyl radical, 1.19c, when thiophosgene was again used
(Scheme 1-6).18
Figure 1-4. 6-Thioxoverdazyl radicals with varying substituent at the N-1 and N-5 positions.
1.4 Inorganic Verdazyl Radicals
In addition to the work performed in the area of 6-oxoverdazyl radicals, Hicks also
contributed to the field of inorganic verdazyl radicals by designing “heteroverdazyl” derivatives
with varying heteroatoms at the 3 and 6 positions. Three types of inorganic verdazyls have been
prepared; 6-phosphaverdazyls 1.22 (Scheme 1-8), 3-phosphaverdazyls 1.24 (Scheme 1-9), and 6-
borataverdazyl radical salts 1.26 (Scheme 1-10). The synthesis of 1.22 begins with the double
addition of methyl hydrazine to RP(O)Cl2, a phosgene equivalent, to give 1.20. Cyclization of
1.20 with PhC(OMe)3 yields the leucoverdazyl 1.21, which is then oxidized to 1.22. The
preparation of 1.24 is very similar to 1.22 and involves the condensation of 1.7a with Ph2PCl3 to
form 1.23 followed by oxidation to 1.24.19 For the synthesis of 1.26, a boratatetrazine
intermediate 1.25 is formed from the complexation of a boron triacetate and a formazan ligand.
Upon reduction by cobaltocene, 1.26 is obtained, marking the first boron containing verdazyl
radical.20 Phosphaverdazyls, on the other hand, made their debut in 1978.21
7
Scheme 1-8. Hicks’ synthesis of 6-phosphaverdazyl (1.22).
Scheme 1-9. Hicks’ synthesis of 3-phosphaverdazyl (1.24).
Scheme 1-10. Hicks’ synthesis of 6-borataverdazyl radical salt (1.26).
1.5 Chemistry and Applications of Verdazyl Radicals
Although verdazyl radicals have been known since the early 1960s, their chemistry and
applications have not been extensively investigated. Their stability has been increased by
protecting the radical through steric means by adding bulky substituent at the C-3 position and/or
by placing the substituent at the C-6 position.7,22,23 Verdazyls, like other radicals, are susceptible
to coupling reactions with alkyl radicals. In such cases, an N-alkylated leucoverdazyl 1.27 is
made (Figure 1-5).24
Figure 1-5. General structure of an N-alkylated leucoverdazyl (1.27).
In 1967, Kuhn reported the oxidative ring opening of C-6-methylene containing verdazyl
radicals by atmospheric oxygen in the presence of activated charcoal (Scheme 1-11). The
product from the reaction was 5-formylformazan, 1.28, and its formation insinuated that the
formazan backbone was preserved in the verdazyl structure.23 In 1972, Neugebauer disclosed a
disproportionation-type thermal decomposition of 1.6b (Scheme 1-12). Heating 1.6b at 80 °C
8
resulted in 1.5b and 1.29a while heating at 200 °C lead to further decomposition of 1.29a to
aniline and 1.29b.25 In 1988, Neugebauer discovered that 1.9b dimerized in the presence of
HCO2H to produce 1.31 in a low yield of 8 % (Scheme 1-13). It was proposed that the dimer
1.31 originated from two intermediate azomethine imines 1.30 and their subsequent [3+3]
cycloaddition reaction.16a
Scheme 1-11. Oxidative ring opening of 1,3,5-triphenylverdazyl radical (1.6b).
Scheme 1-12. Thermolysis of 1,3,5-triphenylverdazyl radical (1.6b).
Scheme 1-13. Dimerization of 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical (1.9b).
Verdazyl radicals have commonly been employed as radical traps and also as spin probes
in polymerization kinetic experiments. In such studies, the long lifetimes of the verdazyl radicals
enable them to be utilized as scavengers to determine initiation rates and concentrations of
propagating radical polymers via ESR.26 In the field of polymers, an attempt to use verdazyl
radicals as mediators for living radical polymerizations (LRP) was made by Yamada, motivated
by the work of Georges et al wherein nitroxide radicals were used to control the polymerization
of styrene. Unfortunately, initial results using a 1,3,5-triphenylverdazyl radical were not
9
promising.27,28 Several years later, using a 1,5-dimethyl-6-oxoverdazyl radical Georges et al
were more successful.29
Within the last fifteen years, verdazyl radicals have transcended from the field of polymer
chemistry to find new applications in inorganic chemistry. In an attempt to construct molecular-
based magnets, verdazyls have been coordinated with various transition metals. Although the
development of verdazyl radicals as magnetic building blocks is at an early stage, the future of
verdazyls in this area is encouraging.30 In recent years, verdazyl radicals have also transitioned
into the discipline of organic chemistry where they have been employed as substrates in the
synthesis of novel heterocyclic compounds. Their emergence marks a cornerstone in the field as
stable radicals have never been used as precursors in organic synthesis.31
1.6 Summary
Verdazyl radicals, unlike typical radicals, are long-lived radicals that can be isolated and
stored for extended periods of time without any significant amount of decomposition.5 The
stability of this class of stable radicals stems from the delocalization of the unshared electron
over the four nitrogen atoms of the backbone.7 Moreover, the radical is sterically shielded by the
R groups at positions 1, 3, and 5.8a Since the serendipitous discovery of the first verdazyl radical
by Kuhn and Trischmann in 1963,7a a number of other verdazyl radicals have been prepared.
This includes the subclass of 6-oxoverdazyls and 6-thioverdazyls, as well as inorganic verdazyls.
Although verdazyls have been known for approximately half a century, their chemistry and
applications have not been extensively investigated, making verdazyl radicals very intriguing
subjects to explore.
1.7 References
(1) Hicks, R. G. Org. Biomol. Chem. 2007, 5, 1321-1338. (2) Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757-771. (3) Forrester, A. R.; Hay, J. M.; Thomson, R. H. Organic Chemistry of Stable Free Radicals;
Academic Press: London, 1968. (4) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 13-19. (5) Koivisto, B. D.; Hicks, R. G. Coord. Chem. Rev. 2005, 249, 2612-2630. (6) Neugebauer, F. A. Angew. Chem. Int. Ed. Engl. 1973, 12, 455-464. (7) (a) Kuhn, R.; Trischmann, H. Angew. Chem. 1963, 75, 294-295. (b) Kuhn, R.;
Trischmann, H. Monatsh. Chem. 1964, 95, 457-479.
10
(8) (a) Williams, D. E. J. Am. Chem. Soc. 1969, 91, 1243-1245. (b) In the paper (ref 8a), the methylene and benzylic carbon are denoted as C(3) and C(6), respectively. However, in this dissertation, the methylene and benzylic carbon will be denoted as C(6) and C(3), respectively, for the intent of maintaining consistency with the atom counting system outlined in 1.2.
(9) Neugebauer, F. A.; Brunner, H.; Hausser, K. H. Tetrahedron 1971, 27, 3623-3628. (10) McConnachie, G.; Neugebauer, F. A. Tetrahedron 1975, 31, 555-560. (11) Williams, D. E. Acta Crystallogr. 1973, B29, 96-102. (12) Neugebauer, F. A.; Fischer. H.; Krieger, C. J. Chem. Perkin Trans. 2 1993, 535-544. (13) Neugebauer, F. A.; Fischer, H. Angew. Chem. Intl. Ed. Engl. 1980, 19, 724-725. (14) Neugebauer, F. A.; Fischer, H.; Siegel, R.; Krieger, C. Chem. Ber. 1983, 116, 3461-3481. (15) Barr, C. L.; Chase, P. A.; Hicks, R. G.; Lemaire, M. T.; Stevens, C. L. J. Org. Chem.
1999, 64, 8893-8897. (16) (a) Neugebauer, F. A.; Fischer, H.; Siegel, R. Chem. Ber. 1988, 121, 815-822. (b)
Barclay, T. M.; Hicks, R. G.; Lemaire, M. T.; Thompson, L. K. Chem. Comm. 2000, 2141-2142. (c) Barclay, T. M.; Hicks, R. G.; Lemaire, M. T.; Thompson, L. K.; Xu, Z. Chem. Comm. 2002, 1688-1689. (d) Gilroy, J. B.; Koivisto, B. D.; McDonald, R.; Ferguson, M. J.; Hicks. R. G. J. Mater. Chem. 2006, 16, 2618-2624. (e) Morita, Y.; Miyazaki, E.; Kawai, J.; Sato, K.; Shiomi, D.; Takui, T.; Nakasuji, K. Polyhedron 2003, 22, 2219-2225. (f) Wu, J-Z.; Bouwman, E.; Reedijk, J.; Mills, A. M.; Spek, A. L. Inorg.
Chim. Acta. 2003, 361, 326-330. (g) Morita, Y.; Nishida, S.; Kobayashi, T.; Fukui, K.; Sato, K.; Shiomi, D.; Takui, T.; Nakasuji, K. Org. Lett. 2004, 6, 1397-1400.
(17) Milcent, R.; Barbier, G. J. Heterocycl. Chem. 1994, 31, 319-324. (18) Pare, E. C.; Brook, D. J.; Brieger, A.; Badik, M.; Schinke, M. Org. Biomol. Chem. 2005,
3, 4258-4261. (19) (a) Hicks, R. G.; Hooper, R. Inorg. Chem. 1999, 38, 284-286. (b) Hicks, R. G.; Ohrstrom,
L.; Patenaude, G. W. Inorg. Chem. 2001, 40, 1865-1870. (20) Gilroy, J. B.; Ferguson, M. J.; McDonald, R.; Patrick, B.O.; Hicks, R. G. Chem. Comm.
2007, 126-128. (21) Kornuta, P. P.; Bobkov, V. N.; Polumbrik, O. M.; Markovskii, L. N. Zh. Obshck. Khim.
1978, 48, 697-698. (22) Neugebauer, F. A.; Trischmann, H. Liebigs Ann. Chem. 1967, 706, 107-111. (23) Kuhn, R.; Neugebauer, F. A.; Trischmann, H. Monatsh. Chem. 1967, 98, 726-730. (24) (a) Kinoshita, M.; Yoshizumi, N.; Imoto, M. Makromol. Chem. 1969, 127, 185-194. (b)
Kinoshita, M.; Miura, Y. Makromol. Chem. 1969, 124, 211-221. (25) Neugebauer, F. A.; Otting, W.; Smith, H. O.; Trischmann, H. Chem. Ber. 1972, 105, 549-
553. (26) (a) Otsu, T.; Yamada, B.; Ishikawa, T. Macromolecules 1991, 24, 415-419. (b) Yamada,
B.; Kageoka, M.; Otsu, T. Macromolecules 1991, 24, 5234-5236. (c) Yamada, B.; Yoshikawa, E.; Shiraishi, K.; Miura, H.; Otsu, T. Polymer 1991, 32, 1892-1896.
(27) Yamada, B.; Nobukane, Y.; Miura, Y. Polym. Bull. (Berlin) 1998, 41, 539-544. (28) (a) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K. Macromolecules
1993, 267, 2987-2988. (b) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K.; Trends Polym. Sci. 1994, 2, 66-72.
11
(29) Chen, E. K. Y.; Teertstra, S. J.; Chan-Seng, D.; Otieno, P.O.; Hicks, R. G.; Georges, M. K. Macromolecules 2007, 40, 8609-8616. (b) Teertstra, S. J.; Chen, E. K. Y.; Chan-Seng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromolecular Symp. 2007, 248, 117-125.
(30) For reviews see: (a) Hicks, R. G. Aus. J. Chem. 2001, 54, 597-600. (b) ref 5 (31) Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org.
Chem. 2008, 4571-4574.
12
2. 1,3-Dipolar Cycloadditions and Azomethine Imines as 1,3-Dipoles
Organic reactions are typically classified as polar or radical reactions, where the
mechanisms proceed through one or more intermediates. Pericyclic reactions, on the other hand,
are concerted processes where all bond breaking and bond forming events take place in one step
via a cyclic transition state.1 One class of pericyclic reactions, cycloadditions, are particularly
appealing to synthetic chemists because of their high yields and high stereo- and regioselectivity.
Of particular interest to our group are the 1,3-dipolar cycloaddition (1,3-DC) reactions, which
involve reactions between a 1,3-dipole, 2.1, and a dipolarophile, 2.2, to afford five-membered
heterocyclic rings 2.3 (Scheme 2-1).1-2 The development of highly efficient methods for the
synthesis of heterocyclic compounds has attracted considerable attention from synthetic chemists
since heterocycles, particularly nitrogen-containing heterocycles, are often found in therapeutic
drugs, natural products, and advanced materials.1 In fact, many commercial synthetic drugs are
nitrogen-containing heterocyclic compounds.3 In this chapter, an overview of 1,3-DC reactions
and the use of azomethine imines as 1,3-dipoles is provided.
Scheme 2-1. General reaction scheme for 1,3-DC reactions.
2.1 1,3-Dipolar Cycloadditions
Pericyclic 1,3-DC reactions are concerted reaction that proceed through a single
transition state, wherein two π bonds are sacrificed to make two new σ bonds, without formation
of any intermediates (Scheme 2-1)1,2,4 1,3-DC reactions are more formally called [3+2]
cycloadditions to indicate the number of atom centers involved in the cycloaddition reaction
between the 1,3-dipole and the dipolarophile.5 1,3-Dipoles, such as 2.1, are isoelectronic with the
allyl anion in which the four π electrons are shared by three atoms. The other reactant, the
dipolarophile 2.2, is a two π electron neutral system and is typically a substituted alkene or
alkyne.2,4,6
1,3-Dipoles can be represented by four resonance structures (Scheme 2-2).4 Of the four
resonance structures, two of them show the dipole in the ylide form (2.1a and 2.1b) where the
13
charges are placed on adjacent atoms, whereas in the zwitterionic form the charges are placed on
the terminal atoms (2.1c and 2.1d). It is worth noting that dipoles are typically illustrated in the
ylide form because in this form all three atoms have a complete octet. In 2.1c and 2.1d, atom a
and c, respectively, have a sextet configuration and thus it is unlikely that these zwitterionic
structures contribute significantly to the overall dipole structure.4,6
Scheme 2-2. Resonance structures for a generic 1,3-dipole.
1,3-Dipoles can be divided into two types: propargyl-allenyl type 2.4 or allyl type 2.1
(Scheme 2-3). Due to the additional π bond in 2.4, a linear geometry of the 1,3-dipole is adopted
as opposed to the bent geometry of 2.1.7 Also, the additional π bond restricts the identity of atom
b in 2.4 to group V elements because only these elements can hold a positive charge while
adopting a quatervalent state. In contrast, atom b of 2.1 is confined to group V and VI elements.
As a result of this limitation, allyl type dipoles are more common.6 Some examples of 1,3-
dipoles of the propargyl-allenyl type and of the allyl type are shown in their ylide form in Figure
2-1.
Scheme 2-3. Propargyl-allenyl type and allyl type 1,3-dipoles.
Figure 2-1. Examples of propargyl-allenyl type and allyl type 1,3-dipoles. The highlighted dipole (2.5) denotes an azomethine imine drawn in the ylide form.
14
Due to the pericyclic nature of 1,3-DC reactions, molecular orbital (MO) theory and the
Woodward-Hoffmann (WH) rules are employed to dictate their feasibility. The WH rules state
that a pericyclic reaction takes place, and thus is termed a symmetry-allowed reaction, when
there is a conservation of symmetry for both the reactant and product orbitals.8 In addition to
predicting the likelihood of a pericyclic reaction, the WH rules also forecast regioselectivity,
stereoselectivity, and reaction rates. However, such a task requires a full MO analysis of the
reactants and product. To alleviate this problem, Fukui developed a simplified model based
strictly on frontier molecular orbitals (FMO). This approach employs perturbation theory and
considers only the interaction between the highest occupied molecular orbital (HOMO) of one
reactant and the lowest unoccupied molecular orbital (LUMO) of the other reactant.9-12 In a
simplistic picture, the HOMO of one species donates electrons to the LUMO of the another
species. For this phenomenon to occur, and thus for cycloaddition reactions to take place, there
are three requirements that must be fulfilled. The first condition requires that the orbital signs of
the 1,3-dipole and dipolarophile’s FMOs match in a symmetry-allowed manner (Figure 2-2a).
The logic behind this is that when the signs of the interacting orbitals match up, the overlap of
the p-orbitals is at its greatest and as a consequence the bonding interaction is maximized. In
cases where the signs do not correlate between the reacting species, the reaction can only
proceed through a non-concerted mechanism.5,12a
Since more than one HOMO-LUMO interactions between the 1,3-dipole and the
dipolarophile is present, one of these interaction will usually dominate (Figure 2-2b). This marks
the second requirement which simply stated says that two species and their associated HOMO or
LUMO will approach each other and react in the direction with the smaller energy difference
(solid arrow).12 This is mathematically expressed by Equation 2-1, where ∆E represents the
stabilization energy, So,u represents the overlap of the occupied and unoccupied orbitals, γo,u
represents the resonance integral that relates orbital overlaps to energies, and εo and εu represents
the energies of the occupied and unoccupied orbitals, respectively.
∆E = 2S2
o,uγ2
o,u / (εo - εu) (Eqn. 2-1)
Since the stabilization energy is inversely proportional to the energy difference (denominator), a
smaller energy gap between the HOMO-LUMO results in a greater stabilization of the cyclic
transition state. This results in a lower energy barrier for the reaction. Thus FMO theory can be
employed to determine the strongest interacting pair of frontier orbitals and subsequently predict
their reactivity based on their energy difference.12-14
15
The final condition needed to ensure a successful cycloaddition reaction is the orientation
of the FMOs of the reacting species in a way that allows for the greatest orbital overlap. This is
achieved by aligning orbitals with the highest coefficients with each other and vice versa (Figure
2-2a). This preference in orientation is mathematically observed in Equation 2-1, where the
stabilization energy is proportional to the square of the orbital overlap (numerator). Therefore, a
greater stabilization is anticipated when there is an interaction between two orbitals with the
largest coefficients and an interaction between two orbitals with the smallest coefficients as
opposed to two interactions both comprising of an orbital with a large coefficient and an orbital
with a small coefficient. This third condition thus allows the regioselectivity of 1,3-DC reactions
to be predicted.12-14
Figure 2-2. FMO diagrams. (a) Matching of the FMOs sign and coefficients. Arbitrary values have been selected for the orbital coefficients. (b) The possible HOMO-LUMO interactions that can occur between the dipole and the dipolarophile. The interactions with the smaller energy gap (solid arrow) will occur due to greater transition state stabilization.
In an extension of the second condition discussed above, the energies of the FMOs for the
dipole and the dipolarophile, which ultimately determine the reactivity of the reaction, are
influenced by the nature of the substituent, as well as, the atomic identity of the reactant’s
backbone. The ability of a substituent to increase or decrease electron repulsion in the reacting
species decreases or increases the FMOs energies, respectively. For example, electron-donating
substituents increase repulsion and thus raise both the HOMO and the LUMO energies of the
reactant while the opposite effect is observed with electron-withdrawing substituents.13-17
Atomic identity also plays a major role in influencing the FMOs’ energy levels as an
atom’s electronegativity is an indirect measure of electron repulsion in the molecule. Introducing
a more electronegative atom for the central atom of a 1,3-dipole (atom b in 2.1) causes the
HOMO energy to decrease slightly while significantly decreasing the LUMO energy. The slight
decrease in the HOMO energy is attributed to the existence of a node through the central atom.
16
Since a node represents an area of no electron density, a small inductive effect is only observed
from the substitution. In regards to the LUMO, since some electron density is present on the
central atom, a substantial decrease in repulsion is expected with an electronegative central atom
resulting in a lowering of the LUMO energy. The opposite trend is observed when a more
electronegative atom is substituted for one of the terminal atoms (atom a or c in 2.1) of a 1,3-
dipole. In the HOMO, where the node is on the central atom, there is more electron density
distributed to the terminal atoms resulting in significant stabilization. In the case of the LUMO,
there is a more even distribution of electron density over the three atoms. As a result, a minor
decrease in the LUMO energy level is observed.18-20 By knowing the relative energies of the
FMOs, predictions can be made to determine the pair of frontier orbitals that is more important
and thus determine the reactivity based on their energy gap.
2.2 Azomethine Imines as 1,3-Dipoles
Azomethine imines are a class of 1,3-dipole of the allyl type consisting of an iminium
center (atom b in 2.1).21 The general backbone of this dipole is illustrated in the ylide form (2.5)
in Figure 2-1. Like other 1,3-dipoles, azomethine imines (2.5) undergo 1,3-DC reactions to
afford saturated or unsaturated five-membered heterocyclic rings (2.7, 2.8) in the presence of an
alkene or an alkyne dipolarophile (2.6), respectively (Scheme 2-4).22
Scheme 2-4. 1,3-DC reaction of an azomethine imine (2.5) with a dipolarophile (2.6).
In addition to intermolecular 1,3-DC reactions, azomethine imines (2.9) can also undergo
intramolecular 1,3-DC reactions to form bicyclic cycloadducts (2.10) in cases where the
dipolarophile is tethered to the dipole (Scheme 2-5).23
Azomethine imines are typically highly reactive species and as a result very few of them
have been isolated. Generally, azomethine imines are generated in situ and subsequently
trapped.21 Their reactive nature is demonstrated by the dimerization reactions that they can
undergo in an effort to attain stability. The formation of these dimers (2.11) involves a [3+3]
cycloaddition between two azomethine imines (2.5) in the absence of a dipolarophile or in the
presence of a weak dipolarophile (Scheme 2-6).2,4,24
17
Scheme 2-5. Intramolecular 1,3-DC reaction.
Scheme 2-6. [3+3] Cycloaddition of an azomethine imine (2.5).
2.3 Summary
The synthetic utility of 1,3-DC reactions represents one of the most efficient methods for
the construction of five-membered heterocyclic compounds. In particular, highly functionalized
N-heterocycles can be prepared by employing azomethine imines as 1,3-dipoles as this enables
the formation of nitrogen-containing cycloadducts. The feasibility, reactivity, and
regioselectivity for the formation of these cycloadducts can be predicted and rationalized in
many cases by applying FMO theory.9-12
2.4 References
(1) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry: Reactions and Synthesis
(Part B), 4th
Ed.; Kluwer Academic/Plenum Publishers: New York, 2001. (2) Huisgen, R. Proc. Chem. Soc. 1961, 357-396. (3) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Towards Heterocycles
and Natural Products (Eds.: A. Padwa, W. H. Pearson); John Wiley & Sons: New York, 2002.
(4) Huisgen, R. Angew. Chem. Int. Ed. Engl., 1963, 2, 565-598. (5) Smith, M. B. Organic Synthesis, 2
nd Ed.; McGraw-Hill, 2001; pp 917-1055.
(6) Huisgen, R. In Introduction, Survey, and Mechanism; Padwa, A., Ed.; 1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New York, 1984; Vol. 1 & 2, pp 1-176.
(7) Huisgen, R. J. Org. Chem. 1976, 41, 403-419. (8) Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc. 1965, 87, 2046-2048. (9) Fukui, K.; Fujimoto, H. Bull. Chem. Soc. Jpn. 1967, 40, 2018-2025. (10) Fukui, K.; Fujimoto, H. Bull. Chem. Soc. Jpn. 1969, 42, 3399. (11) Fukui, K. Acc. Chem. Res. 1971, 4, 57-64.
18
(12) For a review, see: (a) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; John Wiley & Sons: Great Britain, 1976. (b) Ess, D. H.; Jones, G. O.; Houk, K. N. Adv
Synth. Catal. 2006, 348, 2337-2361. (13) Sustmann, R. Pure Appl. Chem. 1974, 40, 569-593. (14) Houk, K. N.; Yamaguchi, K. In Theory of 1,3-Dipolar Cycloadditions; Padwa, A., Eds.;
1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New York, 1984; Vol. 1 & 2, pp 407-450.
(15) Sustmann, R. Tet. Lett. 1971, 29, 2717-2720. (16) Sustmann, R. Tet. Lett. 1971, 29, 2721-2724. (17) Eckell, A.; Huisgen, R.; Sustmann, R.; Wallbillich, G.; Grashey, D.; Spindler, E. Chem.
Ber. 1967, 100, 2192-2213. (18) Houk, K. N. Acc. Chem. Res. 1975, 8, 361-369. (19) Houk, K. N.; Sims, J.; Duke Jr., R. E.; Strozier, R. W.; George, J. K. J. Am. Chem. Soc.
1973, 95, 7287-7301. (20) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301-
7315. (21) Grashey, R. Azomethine Imines. In Azomethine Imines; Padwa, A., Eds.; 1,3-Dipolar
Cycloaddition Chemistry; John Wiley & Sons: New York, 1984; Vol. 1 & 2, pp 733-817. (22) Huisgen, R.; Eckell, A. Tet. Lett. 1960, 12, 5-8. (23) Oppolzer, W. Tetrahedron Lett. 1970, 3091-3094. (24) Huisgen, R. Angew. Chem. Int. Ed. Engl. 1968, 7, 321-406. (25) Schad, P. Ber. Dtsch. Chem. Ges. 1893, 26, 216-217.
19
3. Diversity-Oriented Synthesis
Most biological processes involve very specific protein-protein interactions.1 To elucidate
the nature of these interactions and understand how they modulate a specific biological pathway,
small molecules have been used to target specific binding sites on the proteins in an attempt to
prevent or disrupt the interactions with their binding partner. This has led to the development of
methods directed towards the synthesis of these small molecules which are typically heterocyclic
in nature. The two most prominent processes are target-oriented synthesis (TOS) and diversity-
oriented synthesis (DOS).2-5
3.1 Target-Oriented Synthesis and Diversity-Oriented Synthesis
TOS involves synthesizing individual compounds or a collection of structurally similar
compounds, known as focused libraries. It begins with the selection of a protein target that has
been or is in the process of being characterized, in an effort to gain insights on the topology of
the binding site.3,6,7 Using structure-based rational design, TOS compounds are constructed and
subsequently screened against the protein target to see if any binding occurs.3,5,7 Since TOS
involves selecting a target beforehand, a powerful method called retrosynthetic analysis is used
to devise synthetic pathways from structurally complex products to structurally simple starting
materials.8 An example illustrating retrosynthetic analysis is shown in Figure 3-1. Retrosynthetic
planning reveals that the target compound 3.1 can be formed from the oxy-Cope rearrangement
of 3.2, which can be made from the nucleophilic attack of a vinyl Grignard reagent with 3.3.
Further retrosynthetic analysis indicates that 3.3 can be prepared from the cyclohexadiene 3.4
and the ketene 3.5 via a Diels-Alder reaction.9
Figure 3-1. Retrosynthetic analysis in TOS.
In contrast to TOS, DOS does not focus on a particular target and its resulting biological
pathway. Where TOS libraries consist of structurally similar compounds, which can also be
structurally complex, DOS libraries consist of a collection of structurally complex and diverse
compounds. DOS-derived compounds have the potential to be screened against any protein
20
targets as opposed to a single target.3,5,10 As a consequence of not preselecting a particular target,
retrosynthetic analysis is not employed in DOS. While a highly developed planning algorithm for
DOS has not yet been made available, a guiding strategy known as forward-synthetic analysis is
beginning to emerge. This analysis permits DOS libraries to be designed in a forward direction
rather than a reverse direction, starting from simple and similar starting materials to give
complex and diverse products.10
The goal of DOS is to produce structurally complex and diverse compounds by
employing complexity-generating and diversity-generating processes (Section 3.2 and 3.3).
Structural complexity is an essential feature since small molecules with the ability to perturb
protein-protein interactions to date have been structurally complex. Generally, these structurally
complex small molecules possess rigidifying features (covalent, noncovalent, and nonbonding
interactions) as well as protein-binding constituents that enable them to interact strongly at a
protein binding site, thus disrupting the existing protein-protein interaction and/or preventing
new interactions.3,7 Structural diversity is also an important factor as it increases the likelihood of
discovering new small molecules to probe biological processes and to unveil possible drug
candidates. The increased likelihood is caused by DOS’s intention to occupy a vast region of
chemical space, a space representing all possible small molecules. In contrast, since TOS
libraries consist of structurally similar compounds, they target a specific region of chemical
space. Thus by occupying a broader region of chemical space, DOS has a greater chance of
discovering small molecule modulators.4,11
3.2 Complexity-Generating Processes (Simple ���� Complex)
An efficient method for introducing structural complexity involves employing tandem
reactions in which simple starting materials are used in a complexity-generating reaction to
produce products which are used as substrates in a subsequent complexity-generating reaction.
This product-equal-substrate relationship can be applied repeatedly in a successive fashion
leading to highly complex structures.3,7 This is demonstrated in the Ugi four-component coupling
reaction (Scheme 3-1), where four simple building blocks are reacted together to give 3.6, which
then undergoes an intramolecular Diels-Alder cyclization to give 3.7. The cycloadduct 3.7
undergoes an amide alkylation to yield 3.8 which is finally converted to 3.9 via a ring-opening,
ring-closing olefin metathesis reaction. The multistep synthesis encompasses three complexity-
21
generating reactions (1st, 2nd, 4th step) ending in the formation of the highly complex structure
3.9.12
Scheme 3-1. Use of tandem reactions to generate structural complexity.
3.3 Diversity-Generating Processes (Similar ���� Diverse)
Similarly, diverse structures can be prepared efficiently through tandem reactions where
the products of one diversity-generating reaction are used as substrates in a subsequent diversity-
generating reaction. These structurally diverse compounds can be derived by three methods:
appendage-, stereochemical-, and skeletal diversity-generating process.3,6,7
In the appendage diversity-generating process, the simplest diversity-generating process,
different appendages or building blocks are coupled to a common skeleton called the scaffold.3,6
For example, 3.10 is converted to 3.11 (Scheme 3-2) through a Sonogashira coupling reaction
with a variety of alkyne building blocks (HCCBB1). To take advantage of tandem reactions such
that the diversity of the overall library of compounds is increased, 3.11 is transformed to 3.12 via
an aminolysis reaction. A range of amine building blocks (H2NBB2) can be used for this
reaction, producing a series of different amides attached to the 3.12 scaffold. To further enhance
the structural diversity, an esterification reaction of 3.12 is performed with an assortment of
22
carboxylic acid building blocks (HO2CBB3) to give rise to 3.13. The use of tandem reactions in
these appendage diversity processes requires each of the intermediates (3.11, 3.12) to have a
common reactivity. This property ensures that a set of products can be carried forward in the
subsequent reaction as a set of substrates. For example, the series of 3.11 all shared a lactone
functionality permitting their reaction with the amine building blocks in the following step to
prepare 3.12.13
Scheme 3-2. Diversity-generating process using appendage diversity.
A second type of diversity-generating process involves synthesizing different
stereoisomeric products in an effort to create structural diversity. This process, known as
stereochemical diversity-generating process, can be a very difficult task to achieve due to
selectivity issue. However, the issue can be avoided in cases where the reaction is stereospecific,
producing enantiomeric or diastereomeric products with high selectivity.3,6 In Scheme 3-3, the
chiral substrate 3.14 undergoes an intermolecular Diels-Alder reaction to form 3.15 with high
selectivity. The reaction is under substrate-control because the sterically hindered protecting
group of 3.14 (TIPS) dictates the orientation of the incoming dienophile. As a consequence, only
one diastereomeric product (3.15) is formed.14 In order to form the other diastereomer, 3.16, a
reagent such as a chiral catalyst is needed to nullify the substrate bias and form 3.16 with high
selectivity. Under these circumstances, the reaction is under reagent-control. Though both 3.15
and 3.16 are constitutionally the same, their three-dimensional structures differ and as a result
structural diversity is formed. Unfortunately, for this particular reaction, 3.16 has not yet been
synthesized from 3.14.6,14
23
Scheme 3-3. Diversity-generating process using stereochemical diversity.
Structurally diverse compounds can also be accessed through skeletal diversity-
generating processes, where products are formed with differing scaffolds. This can be
accomplished by two methods, the reagent-based and substrate-based method. In the former
approach, different reagents and reaction conditions are used to convert a common starting
material to a group of products with varying scaffolds.6 For example, 3.17 is used to form 3.18
from an oxidation reaction and 3.19 from treatment with trioxane (Scheme 3-4).15 The reagent-
based approach resembles the process of cell differentiation where different differentiation
factors produce different outcomes and thus this approach is also known as the differentiating
process.6,16
Scheme 3-4. Reagent-based skeletal diversity-generating process.
In contrast to the reagent-based approach, the substrate-based approach employs different
substrates and react them under a common set of reaction conditions. This strategy involves the
use of pre-encoded skeletal information called σ elements, incorporated as part of an appendage,
to dictate the structural outcome of the scaffold. The various appendages and their associated σ
elements are coupled to a common scaffold, which is sensitive to a certain reaction condition.
24
Upon exposure to the reaction condition, the substrates are converted to their corresponding
products as dictated by the σ elements.6,17 For example, 3.20, 3.21, and 3.22 all have a common
furan core but differ in their appendages (Scheme 3-5). When subjected to oxidative and acidic
conditions, 3.20, 3.21, and 3.22 react to form 3.23, 3.24, and 3.25, respectively. As observed, the
three products differ extensively in their skeletal structure.17 This approach resembles the protein
folding phenomenon in which the protein’s three-dimensional structure is governed by the
primary amino acid sequence.18 For this reason, the substrate-based approach is also called the
folding process.6
Scheme 3-5. Substrate-based skeletal diversity-generating process.
3.4 Summary
The DOS approach is a powerful method for providing potential probes in the form of
small molecules to explore biological processes and also to reveal therapeutic targets. Unlike
TOS, DOS does not focus on a particular target. Its objective is to generate a library of
structurally complex and diverse compounds as opposed to TOS libraries, which consist of
structurally complex and similar compounds.2-5 In DOS, structurally complex molecules can be
constructed by employing complexity-generating reactions, while structurally diverse molecules
can be accessed by three different approaches; appendage diversity-generating processes,
stereochemical diversity-generating processes, and skeletal diversity-generating processes.3,6,7
Both structural complexity and diversity can efficiently be achieved by employing tandem
reactions or product-equal-substrate relationships where the products of one reaction are carried
25
forward as substrates in a subsequent reaction. Through the application of these complexity- and
diversity-generating processes the synthetic goals of DOS can be realized.
3.5 References (1) Arkin, M. R.; Wells, J. A. Nat. Rev. Drug Discovery 2004, 3, 301-317. (2) Tan, D. S.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.; Schreiber, S. L. J. Am. Chem.
Soc. 1999, 121, 9073-9087. (3) Schreiber, S. L. Science 2000, 287, 1964-1969. (4) Schreiber, S. L. Chem. Eng. News 2003, 81, 51-61. (5) Tan, D. S. Nature Chem. Bio. 2005, 1, 74-84. (6) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43, 46-58. (7) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-712. (8) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley: New York, 1989. (9) Evans, D. A.; Nelson, J. V. J. Am. Chem. Soc. 1980, 102, 774-782. (10) Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr. Opin. Chem. Biol. 1997, 1,
47-53. (11) Dobson, C. M. Nature 2004, 432, 824-828. (12) Ugi, I.; Domling, A.; Horl, W. Endeavour 1994, 18, 115-122. (13) Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. J. Am. Chem. Soc. 1998, 120,
8565-8566. (14) Micalizio, G. C.; Schreiber, S. L. Angew. Chem. Int. Ed. 2002, 41, 152-154. (15) Micalizio, G. C.; Schreiber, S. L. Angew. Chem. Int. Ed. 2002, 41, 3272-3276. (16) Kuehnle, I.; Goodell, M. A. BMJ. 2002, 325, 372-376. (17) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613-618. (18) Anfinsen, C. B. Science 1973, 181, 223-230.
26
4 Biphenylophanes – Biphenyl-Based Phanes
Cyclophanes are compounds with at least one benzene unit incorporated into a larger ring
system.1 The first of these type of compounds appeared in the literature in 1899 when Pellegrin
allegedly synthesized a [2.2]metacyclophane, 4.1 (Figure 4-1).2 The structure was confirmed
nearly half a century later by Baker et al through molecular weight determination and indirect
experiments involving dehydrogenation to pyrene.3 An X-ray analysis of 4.1 revealed that the
two benzene rings were distorted out-of-plane due to π-electron repulsions similar to what was
observed in the isomeric [2.2]paracyclophane, 4.2.4,5 Although these molecules were structurally
intriguing, their preparation was cumbersome as 4.1 and 4.2 were obtained in 12 %3 and 2.1 %6
yield, respectively. This triggered a movement into pursuing other cyclophanes to explore the
synthetic challenges, unique structures, molecular strain, aromaticity, and reactivity of these
unique molecules. In the last few decades, the main focus has shifted to investigating the
conformational behaviours, structural properties, and role of these molecules as molecular
receptors in host-guest chemistry.
Figure 4-1. Structure of [2.2]metacyclophane (4.1), [2.2]paracyclophane (4.2), and a generic biphenylophane (4.3)
The rapid emergence of bridged aromatic species resulted in the development of a
nomenclature system to more clearly define these compounds. The naming system is based on
the identity of the bridged aromatic component (Table 4-1), the number and size of the bridges,
and the position of the bridge attachment. The number of bridges and the number of bridging
atoms are both represented by numbers set within square brackets and placed before the parent
name. The location of the bridge appendage is indicated by an ortho, meta, para designation or
by a numerical system, both of which are placed between the square brackets and the parent
name. The former system is restricted to benzene and phenyl systems while the latter system can
be applied universally.1 For example, the structure of 4.2 consists of two bridges, both of which
are composed of two atoms, and these bridges are linked, para to each other, on two benzenes.
27
Thus 4.2 is called a [2.2]paracyclophane. The term phane is used to collectively represent all
forms of bridged aromatics.
Table 4-1. Phane names for some types of bridged aromatic compounds.
Identity of Bridged Aromatic Ring Phane Parent Name
Anthracene Anthracenophane
Benzene Cyclophane / Benzenophane
Biphenyl Biphenylophane / Diphenylophane
Ferrocene Ferrocenophane
Furan Furanophane
Naphthalene Naphthalenophane
Pyridine Pyridinophane
Thiazole Thiazolophane
One particular class of phanes, known as biphenylophanes (4.3), consists of a biphenyl
moiety integrated into a macrocyclic ring. With this as a background, we became interested to
see if our new chemistry with verdazyl radicals would lend itself to the synthesis of new
biphenylophanes.
4.1 Biphenylophanes
The chemistry of biphenylophanes was initiated before the emergence of Pellegrin’s
cyclophane 4.1 in 1899. However, many of these early studies lacked sufficient evidence
supporting the proposed structures.1 For example, in 1898 Wedekind reported the synthesis of
4.4 (Figure 4-2), a biphenylophane with five bridging atoms connected to the para, para’
positions of the biphenyl moiety.7 Intuitively, 4.4 would appear to be an implausible structure
because of the short bridge length. Adams and Kornblum subsequently showed that ten bridging
atoms were required to form the appropriate bridge length to the biphenyl unit via the meta,
meta’ positions in 4.5.8 Although the bridging site differs (meta, meta’ vs. para, para’), the latter
study suggested that more than ten atoms are needed to make the bridging connection at the
para, para’ positions in 4.4, thus invalidating the proposed 4.4 structure.
28
Figure 4-2. Structure of Wedekind’s (4.4) and Adams’ and Kornblum’s (4.5) biphenylophane.
To date, there have been a number of reports on the synthesis of different
biphenylophanes where the structures differ in the composition and size of the bridging linkages,
the attachment points on the biphenyl unit, and the number of biphenyl moieties present in the
entire molecule.9 Despite the number of studies conducted on biphenylophanes, this does not
compare to the multitude of studies that focused on cyclophanes. This lack of attention would
largely appear to be due to the greater difficulty associated with the intramolecular ring closure
process needed to form the biphenylophane as a result of a more competitive intermolecular
polymerization process. To circumvent this problem, high dilution techniques have been
employed to favour the intramolecular ring closure process.6a,10
The difficulties endured in the synthesis of biphenylophanes were highlighted in a paper
by Stoddart et al.11 They reported the directed synthesis of 4.8 by the nucleophilic substitution
reaction between 4.6 and 4.7, as well as the directed synthesis of the biphenylophane analogue
4.11 from the nucleophilic substitution reaction between 4.9 and 4.10 (Scheme 4-1). The yield
for 4.8 was 12 % in contrast to 2 % for 4.11 while the reaction time for the formation of 4.8 was
36 hours as opposed to the 14 days needed for 4.11.11
29
Scheme 4-1. Stoddart’s directed synthesis of a cyclophane (4.8) and an analogous biphenylophane (4.11).
4.2 Biphenyl-Stacked Biphenylophanes
A number of structures within the small family of biphenylophanes have biphenyl
moieties arranged in a π-stacked orientation – face-to-face, edge-to-face, or slip stacked. These
structures are of interest because they exhibit unusual structural and/or conformational
properties.
An example illustrating a fascinating conformational change is the ring-flipping process
of a [2.2](3,3’,4,4’)biphenylophane, 4.12a-d, reported by Reiss and Leach. Low temperature
NMR experiments show two conformers, 4.12a and 4.12b. The more stable conformer is 4.12a
while the less stable one is 4.12b due to the increased strain in both bond angle and length. It was
proposed that their interconversion occurred through a ring-flipping process involving two other
conformers, 4.12c and 4.12d, which are degenerate with 4.12b and 4.12a, respectively. The ring-
flipping process is believed to occur by both a concerted and a two-step process (Figure 4-3). In
the concerted process, disrotation of ring A and B interconvert the degenerate pair, 4.12a and
4.12d, while the conrotation of ring A and B interconvert the other degenerate pair, 4.12b and
4.12c. In the two-step process, the interconversion between 4.12a and 4.12d proceeds through a
4.12b or 4.12c intermediate via a stepwise rotation of the A and B ring in two discrete steps.
30
Likewise, the interconversion between the other degenerate pair, 4.12b and 4.12c, occurs
through a 4.12a or 4.12d intermediate via a tandem rotation of the A and B ring in two discrete
steps. Intermediate 4.12e was speculated to be the transition state for both the concerted
conrotatory and disrotatory processes even though the two degenerate pairs of conformers are of
different energies.12
A
BB
B
A
A
Disrotation
of Ring A
and B
Conrotation
of Ring A
and B
Rotation
of Ring B
Rotation
of Ring A
Rotation
of Ring A
Rotation
of Ring B
4.12a 4.12b
4.12c 4.12d
4.12e
BBA
A
Disrotation
of Ring A
and B
Conrotation
of Ring A
and B
Figure 4-3. Proposed conformational ring-flipping of a [2.2](3,3’,4,4’)biphenylophane.
In an effort to unravel new conformational behaviours of biphenylophanes, Lai et al
discovered that the biphenyl units of 4.13, 4.14, and 4.15 (Figure 4-4) were conformationally
rigid up to a temperature of 443 K. The observation was made based on the fact that the eight
aromatic protons of the biphenyl moiety were magnetically non-equivalent and gave complex
multiple coupling patterns. This result could only be explained by a restricted rotation of the
biphenyl unit.13
Figure 4-4. Structure of dithiabiphenylophane 4.13, 4.14, and 4.15.
Interesting structural studies have been observed in the work by Iyoda et al, where they
presented the X-ray results of a biphenyl-stacked phane 4.16 (Figure 4-5). The analysis revealed
the presence of a strong π-π interaction between the two face-to-face biphenyl-stacked units as a
31
result of π electrons overlap. A resulting ring strain was shown to be reduced by bending the six
bonds as highlighted.14
Figure 4-5. Structure of a face-to-face biphenyl-stacked phane (4.16).
Also worthy was the publication by Tani et al wherein they synthesized two isomeric
biphenylophanes, 4.19 and 4.20, as well as their corresponding deselenated biphenylophanes
4.21 and 4.22 in a one-pot synthesis via a coupling reaction between 4.17 and 4.18. The
isomeric pairs adopted different stacking patterns where one assumed a parallel-orientation
conformation (4.19 and 4.21) while the other assumed a cross-orientation conformation (4.20
and 4.22).15
Scheme 4-2. One-pot synthesis of a parallel- (4.19, 4.21) and cross-oriented conformation biphenylophane (4.20, 4.22).
Br
Br
Br
Br
NCSe
NCSe
SeCN
SeCN
OMeMeO
NaBH4
Se Se
OMeMeO
Se Se
Se Se
OMeMeO
Se
OMe
SeMeO
OMeMeO
+
+
P(NMe2)3h
+
4.17 4.18
4.19 4.20
4.21 4.22
32
4.3 Summary
Bridged aromatic molecules or phanes have been known for over a century and in the
course of this time insights have been obtained regarding their chemical, physicochemical, and
biological properties. Within the class of phanes are compounds with bridged biphenyl nuclei
and these species are refer to as biphenylophanes. Only a small number of these compounds have
been synthesized and investigated relative to the numerous case studies concentrated on
cyclophanes. Even rarer are biphenylophanes with biphenyl-stacked moieties. It is speculated
that their neglect is the result of the difficulties associated with their preparation. Nevertheless,
structural and conformational analysis of these scarce molecules has unveiled some very
compelling results.
4.4 References
(1) Smith, B. H. Bridged Aromatic Compounds; Academic Press Inc.: New York, 1964. (2) Pellegrin, M. Rec. Trav. Chim. 1899, 18, 457-465. (3) (a) Baker, W.; McOmie, J. F. W.; Norman, J. M. Chem. Ind. 1950, 77-77. (b) Baker, W.;
McOmie, J. F. W.; Norman, J. M. J. Chem. Soc. 1951, 1114-1118. (4) Brown, C. J. J. Chem. Soc. 1953, 3278-3285. (5) Brown, C. J.; Farthing, A. C. Nature 1949, 164, 915-916. (6) (a) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691-5704. (b) In the original
paper (ref 5), Brown and Farthing reported that 4.2 was formed in trace amounts whereas Cram and Steinberg reported a 2.1 % yield.
(7) Wedekind, E. Ann. 1898, 300, 239. (8) Adams, R.; Kornblum, N. J. Am. Chem. Soc. 1941, 63, 188-200. (9) (a) Stetter, H.; Roos, E.-E. Chem. Ber. Recl. 1955, 88, 1390-1395. (b) Allinger, N. L.; Da
Rooge, M. A.; Hermann, R. B. J. Am. Chem. Soc. 1961, 83, 1974-1978. (c) Fujimoto, M.; Sato, T.; Hata, K. Bull. Chem. Soc. Jpn. 1967, 40, 600-605. (d) Haenel, M.; Staab, H. A. Tetrahedron Lett. 1970, 41, 3585-3588. (e) Staab, H. A.; Haenel, M. Chem. Ber. 1973, 106, 2190-2202. (f) Jessup, P. J.; Reiss, J. A. Aust. J. Chem. 1976, 29, 1267-1275. (g) Thulin, B.; Wennerstrom, O.; Somfai, I.; Chmielarz, B. Acta Chem. Scand. Ser. B 1977, 31, 135-140. (h) Nishimura, J.; Doi, H.; Ueda, E.; Ohbayashi, A.; Oku, A. J. Am. Chem.
Soc. 1987, 109, 5293-5295. (i) Vogtle, F.; Kadei, K. Chem. Ber. 1991, 124, 903-907. (j) Nakamura, Y.; Mita, T.; Nishimura, J. Synlett 1995, 957-958. (k) Breidenbach, S.; Harren, J.; Neumann, S.; Nieger, M.; Rissanen, K.; Vogtle, F. J. Chem. Soc. Perkin
Trans. 1 1996, 2061-2067. (l) Lai, Y.-H.; Ang, S.-G.; Wong, S.-Y. Tetrahedron Lett. 1997, 38, 2553-2556. (m) Laufenberg, S.; Feuerbacher, N.; Pischel, I.; Borsch, O.; Nieger, M.; Vogtle, F. Liebigs Ann. Recl. 1997, 1901-1906. (n) van Eis, M. J.; de Kanter, F. J. J.; de Wolf, W. H.; Bickelhaupt, F. J. Org. Chem. 1997, 62, 7090-7091. (o) van Eis, M. J.; de Kanter, F. J. J.; de Wolf, W. H.; Bickelhaupt, F. J. Am. Chem. Soc. 1998, 120, 3371-3375. (p) Burguete, M. I.; Diaz, P.; Garcia-Espana, E.; Luis, S. V.; Miravet, J. F.; Querol, M.; Ramierz, J. A. Chem. Commun. 1999, 649-650.
33
(q) Niederalt, C.; Grimme, S.; Peyerimhoff, S. D.; Sobanski, A.; Vogtle, F.; Lutz, M.; Spek, A. L.; van Eis, M. J.; de Wolf, W. H.; Bickelhaupt, F. Tetrahedron: Asymmetry 1999, 10, 2153-2164. (r) Schwierz, H.; Vogtle, F. J. Inclusion Phenom. Macrocyclic
Chem. 2000, 37, 309-329. (s) Burguete, M. I.; Escuder, B.; Garcia-Espana, E.; Lopez, L.; Luis, S. V.; Miravet, J. F.; Querol, M. Tetrahedron Lett. 2002, 43, 1817-1819. (t) Benniston, A. C.; Clegg, W.; Harriman, A.; Harrington, R. W.; Li, P.; Sams, C. Tetrahedron Lett. 2003, 44, 2665-2667. (u) Yamaji, M.; Tsukada, T.; Shizuka, H.; Nishimura, J. Chem. Phys. Lett. 2008, 460, 474-477. (v) Kai, H.; Ohshita, J.; Ohara, S.; Nakayama, N.; Kunai, A.; Lee, I.-S.; Kwak, Y.-W. J. Organomet. Chem. 2008, 693, 3490-3494. (w) Wald, P.; Schneider, H.-J. Eur. J. Org. Chem. 2009, 3450-3453.
(10) Cope, A. C.; Herrick, E. C. J. Am. Chem. Soc. 1950, 72, 983-987. (11) (a) Asakawa, M.; Ashton, P. R.; Menzer, S.; Raymo, F. M.; Stoddart, J. F.; White, A. J.
P.; Williams, D. J. Chem. Eur. J. 1996, 2, 877-893. (b) Ashton, P. R.; Menzer, S.; Raymo, F. M.; Shimizu, G. K. H.; Stoddart, J. F.; Williams, D. J. Chem. Commun. 1996, 487-490. (c) Raymo, F. M.; Stoddart, J. F. Pure. Appl. Chem. 1996, 68, 313-322.
(12) (a) Leach, D.N.; Reiss, J.A. Tetrahedron Lett. 1979, 46, 4501-4504. (b) Leach, D.N.; Reiss, J.A. Aust. J. Chem. 1980, 33, 823-831.
(13) Lai, Y.-H.; Wong, S.-Y.; Chang, H.-Y. Tetrahedron 1993, 49, 669-676. (14) Iyoda, M.; Konda, T.; Nakao, K.; Hara, K.; Kuwatani, Y.; Yoshida, M.; Matsuyama, H.
Org. Lett. 2000, 2, 2081-2083. (15) (a) Tani, K.; Seo, H.; Maeda, M.; Imagawa, K.; Nishiwaki, N.; Ariga, M.; Tohda, Y.;
Higuchi, H.; Kuma, H. Tetrahedron Lett. 1995, 36, 1883-1886. (b) Higuchi, H.; Misumi, S. Tetrahedron Lett. 1982, 23, 5571-5574.
34
5. The Emergence of Verdazyl Radicals as Substrates for 1,3-Dipolar Cycloaddition Reactions
5.1 Introduction
In 1993, Georges et al demonstrated the control of styrene polymerization using nitroxide
stable free radicals as mediators. This type of polymerization system, known as stable free-
radical polymerization (SFRP), produces polymers with predictable molecular weights and
narrow molecular weight distributions, which are important parameters that must be controlled to
allow the design of precision polymers.1 In an attempt to extend this work and address some of
the problems encountered with nitroxide radicals at the time, as for example, their inability to
enable the polymerization of acrylate monomers efficiently, Yamada et al studied the use of
verdazyl radicals.2 Unfortunately, their results using a 1,3,5-triphenylverdazyl radical were not
promising. Polymers with very high molecular weights and broad polydispersities were
produced. Further analysis of the polymers showed most of the chains was irreversibly
terminated. Several years later, Georges et al revisited verdazyl radicals as mediators for LRP.
Based on the concept that nitroxide-mediated LRPs are often initiated with BST unimolecular
initiators (5.1), an effort was made to attempt these polymerizations with the verdazyl analogue
of 5.1, the BSV unimolecular initiators (5.2). These unimolecular initiators, also known as
unimers, are composed of three building blocks; a stable radical unit, a monomer unit, and an
initiator unit. For example, the BST unimer 5.1 consists of a benzoyloxy moiety, a styrene
moiety, and a 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO) moiety.4
Figure 5-1. Structure of BST unimer (5.1) and BSV unimer (5.2).
To determine the feasibility of verdazyl-mediated polymerization, the synthesis of the
BSV unimer 5.2 was initiated by reacting 5.3 with BPO in styrene at room temperature under an
atmosphere of nitrogen (Scheme 5-1). The reaction only afforded a 10 % yield of 5.2. It turned
out that the major product isolated from the reaction was 5.4, formed in 28 % yield. This finding
was intriguing because not only did 5.4 represent a novel structure with a pyrazolotetrazinanone
functionality, but its formation was derived from a stable radical, molecules which had never
35
previously been employed as substrates for organic synthesis.5 It is worth noting that 5.2 was
eventually successfully prepared through an exchange reaction between BST unimers and 1,5-
dimethyl-6-oxoverdazyl radicals where the TEMPO component of the BST unimer was
displaced by the verdazyl radical. Employing 5.2 as mediators, permitted the formation of
styrene and n-butyl acrylate homopolymers to occur in a living manner.3
However, the formation of 5.4 was intriguing and opened the door to the possibility of
using stable radicals as substrates for organic synthesis. Considering the fact that many synthetic
drugs are heterocyclic compounds that contain nitrogen and the fact that this new chemistry
offered the possibility of synthesizing many new nitrogen-containing heterocyclic scaffolds that
could be universally tested for drug activity, our lab was inspired to develop the chemistry
behind its unique synthetic utility in heterocyclic syntheses.
Scheme 5-1. Attempted synthesis of a BSV unimer (5.2).
5.2 Development of the 1,3-DC Reaction Initiated with Verdazyl Radicals
The formation of 5.4 was postulated to occur by a 1,3-DC reaction between the
azomethine imine 5.7 and the styrene dipolarophile, where the former species was generated in
situ from a disproportionation-type hydrogen abstraction between two molecules of 5.3 (Scheme
5-2). The generation of 5.7 from the disproportionation reaction was supported by DFT
calculations computed at the B3LYP/6-31G(d) level. The subsequent 1,3-DC reaction of 5.7 with
styrene produced only the regioisomer 5.4. Regioisomer 5.5 was absent from the reaction
mixture strongly indicating that the reaction to produce 5.4 was a concerted pericyclic reaction.5
The suggested mechanism for the reaction is summarized in Scheme 5-2.
The proposed mechanism implies that BPO is not involved in the synthesis of 5.4. This is
in fact the case, which was confirmed by repeating the reaction sequence in the absence of BPO
and obtaining the same results as the reaction previously described in which BPO was present.
The mechanism also suggests that a leucoverdazyl, 5.6, is formed from the disproportionation
reaction.5 The presence of 5.6 was indirectly confirmed by alkylating 5.6 with benzyl chloride in
36
the presence of sodium hydride to produce the N-benzyl leucoverdazyl product. Since
leucoverdazyls are known to be oxidized in the presence of oxygen to the corresponding
verdazyl radical,6 the reaction was carried out in oxygen to regenerate 5.3, which can re-enter the
reaction sequence and result in an improvement in the yield of 5.4.5
Scheme 5-2. Proposed mechanism for the formation of the cycloadduct 5.4.
The 1,3-DC reaction of 5.3, via a 5.7 intermediate, was extended to scope out the various
type of olefinic substrates or dipolarophiles that can be employed. Some of the results are
displayed in Table 5-1. Generally, reactions proceeded in high yields with electron poor olefins
(Entries 1-4) and in low or no yields with unactivated or electron rich olefins. It appeared that
steric hindrance imposed either at the alkoxy functional group (Entry 2) or at the α-carbon (Entry
3) of the olefin was not an influential factor in the formation of the corresponding cycloadducts.
In instances where the olefin was in a specific stereochemical configuration, the reaction
occurred with conservation of stereochemistry (Entries 5, 6). Cyclic olefins have also been
utilized and they reacted to afford tricyclic compounds (Entry 7). Reactions with isoprene
produced two products, 5.15a and 5.15b, where 5.15a was afforded in greater yield due to a
faster reaction of the disubstituted double bond relative to the monosubstituted double bond. All
reactions discussed above, afforded just one regioisomeric cycloadduct except for entries 1 and 2
where less than 1 % of the other regioisomeric cycloadduct was formed. This outcome, coupled
with the high stereospecificity of the reaction, was in accordance with the 1,3-DC mechanism
that had been proposed.5
37
Table 5-1. Some results from the 1,3-DC reaction between 5.3 with various dipolarophiles.
N
N N
N
O
Ph
N
N N
N
O
Ph
R
R 1) O2, 10 min.
2) r.t., 24 h+
5.3 5.8 - 5.15
N
N N
N
O
Ph COOMe
OMe
O
OtBu
O
OMe
O
CN
CO2Et
EtO2C
CO2Et
CO2Et
N
O
O
N
N N
N
O
Ph COOtBu
N
N N
N
O
Ph COOMe
N
N N
N
O
Ph CN
N
N N
N
O
Ph COOEt
N
N N
N
O
Ph COOEt
N
N N
N
O
Ph
COOEt
COOEt
N
O
O
Dipolarophile Cycloadduct Isolated YieldEntry
1
2
3
4
5
6
7
74 %
82 %
84 %
62 %
83%
42%
56 %
5.8
5.9
5.10
5.11
5.12
5.13
5.14
N
N N
N
O
Ph
5.15aN
N N
N
O
Ph
5.15b
8 40 %
(3:2)
38
It is interesting to note that pyrazolotetrazinanone cycloadducts (5.16) with an acidic α-
hydrogen can undergo base-induced rearrangement reactions to afford pyrazolotriazinones
(5.17), which can further rearrange to the triazoles (5.18) in the presence of a nucleophilic base
(Scheme 5-3). The formation of 5.17 has been proposed to occur by an initial deprotonation of
the α-hydrogen to form the carbanion 5.19, which intramolecularly attacks the carbonyl centre of
the urea moiety to generate the highly strained four-membered intermediate 5.20 (Scheme 5-4).
Spontaneous decomposition of 5.20 gives 5.21, which is protonated to afford 5.17.7
The mechanism for the formation of 5.18 is surmised to proceed through the intermediate
5.17 (Scheme 5-5). The nucleophile, denoted as a nucleophilic alcohol in Scheme 5-5, undergoes
a nucleophilic addition reaction to the carbonyl centre of the amide functional group to give 5.22.
Ring opening of 5.22 results in the formation of 5.23, where the amine anion intramolecularly
adds to the ester group to form the five-membered 5.24. Ring opening of 5.24 forms the
carbamate 5.25, where the carbanion attacks the diazene centre to yield 5.26. The following
aromatization of 5.26 affords the triazole 5.18.7
Scheme 5-3. Rearrangement of pyrazolotetrazinanones (5.16).
N
N N
N
O
Ph R
-hydrogen
N
N N
O
Ph
NH
R
N
N
N
Ph
NH
OR'
O
-OR
5.16 5.17 5.18
base
-OR
Scheme 5-4. Proposed mechanism for pyrazolotriazinones formation.
39
Scheme 5-5. Proposed mechanism for triazoles formation.
5.3 Summary
Like many discoveries, the formation of structurally unique heterocyclic compounds
derived from verdazyl radicals represented a serendipitous finding. The novelty behind this
chemistry was that not only can verdazyl radicals be employed to incorporate an unique
pyrazolotetrazinanone functionality into these heterocycles, but their utility in organic synthesis
have never been reported in literature. This strategy presents the possibility of synthesizing many
new nitrogen-containing heterocyclic scaffolds, a feature that is found in all synthetic drugs. It
has been proposed that these nitrogen-containing heterocycles originated from an intermediate
azomethine imine, formed from a disproportionation-type hydrogen abstraction between two
molecules of 5.3, and its subsequent 1,3-DC reaction with various dipolarophiles. In an attempt
to pioneer the work behind verdazyl radicals as precursors for 1,3-DC reactions, the reaction
conditions were optimized and the scope of olefinic substrates were subsequently investigated.
The resulting high regioselectivity and stereospecificity of the reactions supports the proposed
1,3-DC mechanism.5 Furthermore these pyrazolotetrazinanones have been shown to undergo
base-mediated and nucleophilic-mediated rearrangement reactions to afford pyrazolotriazinones
and triazoles, respectively,7 thus providing additional opportunities to access nitrogen-containing
heterocyclic scaffolds.
40
5.4 References
(1) (a) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K. Macromolecules 1993, 267, 2987-2988. (b) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K.; Trends Polym. Sci. 1994, 2, 66-72.
(2) Yamada, B.; Nobukane, Y.; Miura, Y. Polym. Bull. (Berlin) 1998, 41, 539-544. (3) Chen, E. K. Y.; Teertstra, S. J.; Chan-Seng, D.; Otieno, P.O.; Hicks, R. G.; Georges, M.
K. Macromolecules 2007, 40, 8609-8616. (b) Teertstra, S. J.; Chen, E. K. Y.; Chan-Seng, D.; Otieno, P. O.; Hicks, R. G.; Georges, M. K. Macromolecular Symp. 2007, 248, 117-125.
(4) Hawker, C. J. J. Am. Chem. Soc. 1994, 116, 11185-11186. (5) Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org.
Chem. 2008, 4571-4574. (6) (a) Kuhn, R.; Trischmann, H. Monatsh. Chem. 1964, 95, 457-479. (b) Neugebauer, F. A.
Angew. Chem. Int. Ed. Engl. 1973, 12, 455-464. (7) Chen, E. K. Y.; Bancerz, M.; Georges, M. K. Publication in Progress.
41
6. Application of Diversity-Oriented Synthesis to Verdazyl Radicals and their Derived Heterocycles
6.1 Introduction and Objective
Verdazyl radicals have recently been employed as substrates for organic synthesis to
afford unique pyrazolotetrazinanone cycloadducts.1 Through careful planning, these
cycloadducts can be designed with derivatizable functionality allowing for further modifications
to be made to the scaffold. In addition, it has been demonstrated that the pyrazolotetrazinanone
scaffold can be coaxed into undergoing base or nucleophile induced rearrangements to afford
pyrazolotriazinones or triazoles, respectively, producing second generation molecular scaffolds
(Scheme 5-3).2 These features make verdazyl radicals and their derived heterocycles appealing
candidates for DOS.
The formation of pyrazolotetrazinanone cycloadducts has been proposed to occur through
the intermediacy of an azomethine imine, which undergoes a 1,3-DC reaction with various
dipolarophiles (Scheme 5-2). 1,3-DC reactions represent complexity-generating reactions as they
produce in one step structurally complex products (Scheme 6-1). These first generation
heterocyclic products can react further if derivatizable sites are present. For example, a Suzuki
cross-coupling reaction, also a complexity-generating reaction, can be performed with an aryl
bromide moiety present in the cycloadduct. This succeeding complexity-generating reaction
enables a greater degree of complexity to be introduced into the newly formed structures. Since
these pyrazolotetrazinanone compounds have been shown to rearrange, their employment
following Suzuki coupling reactions makes effective use of tandem reactions to efficiently
produce structurally complex molecules.
Similarly, diverse verdazyl-originated structures can be efficiently prepared by adopting
tandem reactions in an iterative manner. In the 1,3-DC reaction, various acrylates and
acrylamides can be utilized as dipolarophiles to produce a collection of products, as illustrated in
Scheme 6-1. Then one of the initially formed products, such as 6.2, can diverge into two separate
pathways, where one pathway involves converting the ester of 6.2 to various amides by using a
series of different amines. The other pathway could involve Suzuki coupling reactions of 6.2
with a variety of arylboronic acids. The same coupling reaction could also be applied to both sets
of 6.6 and 6.9 to give 6.7 and 6.10, respectively. The Suzuki products, 6.3, 6.7, and 6.10, can all
42
undergo base-induced rearrangements to afford the pyrazolotriazinones 6.4, 6.8, and 6.11,
respectively, while their nucleophile induced rearrangements could yield the triazole 6.5.
Scheme 6-1. Planning of DOS to verdazyl radicals and their derived heterocycles.
N
N N
N
O
N
N N
N
O
COOBB1
Br
Br
O-BB1
O
N
N N
N
O
CONHBB2
Br
NH-BB2
O
N
N N
N
O
CONHBB3
Br
H2N-BB3
N
N
N
NH
O
NuBB5
BB4
N
N
N
NH
O
NuBB5
BB4
N
N
N
NH
O
NuBB5
BB4N
N N
N
O
COOBB1
BB4
N
N N
N
O
CONHBB2
BB4
N
N N
N
O
CONHBB3
BB4
(Acrylates)
(Acrylamides)
(HO)2B
BB4
Base
Base
Base
B(OH)2
BB4
B(OH)2
BB4
1,3-DC
N
N N
O
NH
BB4
COOBB1
Nu-BB5
N
N N
O
NH
BB4
CONHBB2
Nu-BB5
N
N N
O
NH
BB4
CONHBB3
Nu-BB5
6.1
6.2
6.3
6.4
6.5
6.6 6.7
6.5
6.8
6.9 6.10
6.5
6.11
The proposed DOS strategy discussed above takes into account two different types of
diversity-generating processes. In all reactions other than the rearrangement reactions, appendage
diversity is produced by using various reagent building blocks (BB1, BB2, BB3, BB4, BB5) and
coupling them to the scaffold. The second form of structural diversity generation is displayed in
both the base and nucleophile induced rearrangement reactions, where skeletal diversity is
created. Specifically, a reagent-based skeletal diversification is illustrated where different
reagents and reaction conditions are employed to convert a common substrate to products with
differing scaffolds.
In this section the approach of DOS to verdazyl radicals and their derived heterocycles
will be applied and discussed. The objective of the investigation is fourfold: (1) to generate a
43
library of structurally complex and diverse verdazyl-derived molecules, (2) to examine the
versatility, or limitations, of verdazyl radicals as substrates for organic synthesis, (3) to
determine the feasibility of the DOS application to this system, and (4) to screen the library of
compounds for any therapeutic effects or lead compounds.
6.2 Experiment Section
6.2.1 Materials and Equipment
Chemicals. All reagents and ACS grade solvents were purchased from Sigma-Aldrich or
VWR unless otherwise stated. Column chromatography was performed with Silica Gel P60
(mesh size 40-63 µm) obtained from Silicycle. Thin layer chromatography (TLC) was performed
on aluminum plates coated with silica (pore size of 60Å) containing a fluorescent indicator,
obtained from EMD Chemicals, and visualized under UV (254 nm) light.
General. NMR spectra were acquired on a Bruker Avance III spectrometer at 23 °C,
operating at 400 MHz for 1H NMR and 100 MHz for 13C NMR or a Varian Unity INOVA-500
spectrometer at variable temperatures as stated, operating at 500 MHz for 1H NMR and 125 MHz
for 13C NMR. Chemical shifts (δ) are reported in parts per million (ppm) relative to
tetramethylsilane (0 ppm) for 1H NMR spectra and CDCl3 (77.0 ppm) for 13C NMR. Coupling
constants (J) are reported in hertz (Hz). Spin multiplicities are designated by the following
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).
Accurate mass determinations (HRMS) were carried out by the AIMS lab, Department of
Chemistry, University of Toronto using a Micromass 70S-250 sector mass spectrometer or
ABI/Sciex Qstar mass spectrometer. Mass spectrometry was performed on an AB/Sciex QStar
mass spectrometer with an ESI source, MS/MS and accurate mass capabilities, associated with
an Agilent 1100 capillary LC system. Microwave irradiations were carried out in a Biotage
Initiator 2.5 in a sealed microwave vial.
6.2.2 Synthesis of N,N’-dimethylcarbonohydrazide (1.7a):
44
N,N’-dimethylcarbonohydrazide (1.7a) was prepared according to a slightly modified
literature procedure. To a three neck round bottom flask equipped with a mechanical stirrer, an
addition funnel, and a gas inlet was added methyl hydrazine (28.0 g, 606 mmol, 12 equiv) in
dichloromethane (300 mL). To the addition funnel was added a solution of triphosgene (15.0 g,
50.6 mmol, 1 equiv) in dichloromethane (225 mL). The methyl hydrazine solution was cooled to
-78 °C by immersing the reaction flask into a dry ice/acetone bath and then purged with nitrogen
for twenty minutes with stirring. The solution of triphosgene was added drop wise over a period
of 4-5 hours under nitrogen, while maintaining a temperature of -78 °C. Once the addition was
complete, the reaction mixture was allowed to warm up to room temperature with stirring over
three hours. The reaction mixture was filtered to remove the white hydrazine salt and the filtrate
was concentrated under reduced pressure to afford 1.7a (15.7 g, 87 %) as a yellow oil. 1H NMR
(500 MHz, CDCl3) δ 4.14 (br, s, 4H), 3.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 166.0, 42.0;
HRMS (ESI) m/z [M + H]+ calcd for 119.0927; found, 119.0931.
6.2.3 Synthesis of 1,5-dimethyl-3-(3-bromophenyl)-1,2,4,5-tetrazinan-6-one (6.12):
To a round bottom flask equipped with an addition funnel was added 1.7a (1.00 g, 8.46
mmol, 1.1 equiv) in methanol (20 mL). The reaction flask was immersed into an oil bath where
the oil bath was heated to 70 °C with stirring. A solution of 3-bromobenzaldehyde (1.40 g, 7.57
mmol, 1 equiv) in methanol (20 mL) was added drop wise every five seconds via the addition
funnel. The reaction was monitored by TLC (silica, ethyl acetate/methanol 95:5) and the reaction
flask was removed from the heat when nearly all of the aldehyde had reacted. The reaction
mixture was concentrated under reduced pressure and purified by column chromatography
(silica, ethyl acetate/methanol 95:5) to give 6.12 as an orange-yellow solid (2.16 g, 50 %). 1H
NMR (400 MHz, CDCl3) δ 7.74 (br, s, 1H), 7.50 (t, J = 8.46 Hz, 2H), 7.29-7.24 (m, 1H), 5.05
(br, s, 1H), 4.41 (br, s, 2H), 3.16 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 155.5, 137.5, 131.8,
130.2, 129.9, 125.3, 122.8, 68.7, 38.2.
45
6.2.4 Synthesis of 1,5-dimethyl-3-(3-bromophenyl)-6-oxoverdazyl radical (6.1):
To a solution of 6.12 (1.00 g, 3.51 mmol, 1 equiv) in ethyl acetate (200 mL) was added a
saturated solution of sodium (meta)periodate (1.88 g, 8.78 mmol, 2.5 equiv) in water. The
biphasic system was allowed to stir where a noticeable color change of the organic layer to red
was observed. The reaction was monitored by TLC (silica, ethyl acetate/methanol 95:5) until all
of 6.12 had reacted. The aqueous layer was removed and extracted with ethyl acetate (3 x 20
mL). The combined organic layers was dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure to give 6.1 (0.99 g, 85 %) as a red solid.
6.2.5 General procedure for 1,3-dipolar cycloaddition reactions:
In a general procedure, 6.1 (100 mg, 0.35 mmol, 1 equiv) was dissolved in a minimal
volume of toluene in a round bottom flask equipped with a vigreux condenser. To the round
bottom flask was added an excess of the dipolarophile (3.50 mmol, 10 equiv). The reaction
mixture was allowed to reflux at 110 °C with stirring for 3 h under an atmosphere of oxygen.
Excess dipolarophile was removed under reduced pressure and the cycloadducts were purified by
silica gel column chromatography.
6.2.6 Synthesis of methyl 4-(3-bromophenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (6.13):
The title compound 6.13 was prepared in accordance with the general procedure using
methyl acrylate as the dipolarophile. The product was purified by column chromatography (3:2
ethyl acetate/hexane) to afford 6.13 as yellow crystals (77 mg, 60 %). 1H NMR (400 MHz,
46
CDCl3) δ 7.80 (br, t, J = 1.78 Hz, 1H), 7.61-7.54 (m, 2H), 7.27 (t, J = 7.90 Hz, 1H), 4.25-4.15
(m, 2H), 3.60 (s, 3H), 3.54-3.45 (m, 1H), 3.36 (s, 3H), 2.50-2.39 (m, 1H), 2.32-2.20 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 171.2, 154.1, 144.4, 133.8, 133.1, 130.4, 130.2, 126.1, 122.8, 62.2,
52.5, 44.2, 36.9, 29.8.
6.2.7 Synthesis of methyl 4-(3-bromophenyl)-2,6-dimethyl-1-oxo-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (6.14):
The title compound 6.14 was prepared in accordance with the general procedure using
methyl metacrylate as the dipolarophile. The product was purified by column chromatography
(3:2 ethyl acetate/hexane) to afford 6.14 as a pale yellow powder (73 mg, 55 %). 1H NMR (400
MHz, CDCl3) δ 7.79 (br, t, J = 1.80 Hz, 1H), 7.60 (br, d, J = 7.88 Hz, 1H), 7.55 (br, d, J = 7.91
Hz, 1H), 7.25 (t, J = 7.94 Hz, 1H), 3.94-3.80 (m, 2H), 3.67 (s, 3H), 3.34 (s, 3H), 2.58-2.49 (m,
1H), 1.96-1.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 172.4, 155.3, 145.1, 134.2, 133.5, 131.1,
129.7, 126.8, 122.2, 69.8, 52.5, 44.3, 38.3, 36.8, 23.2.
6.2.8 Synthesis of 4-(3-bromophenyl)-N,N,2-trimethyl-1-oxo-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (6.15):
N
N N
N
O
Br
CON(CH3)2
N(CH3)2
O
N
N N
N
O
Br
Toluene
110oC, 3 h
6.1 6.15
The title compound 6.15 was prepared in accordance with the general procedure using
N,N-dimethylacrylamide as the dipolarophile. The product was purified by column
chromatography (1:1 ethyl acetate/dichloromethane) to afford 6.15 as yellow crystals (67 mg, 50
%). 1H NMR (400 MHz, CDCl3) δ 7.81 (br, t, J = 1.73 Hz, 1H), 7.60 (br, d, J = 7.85 Hz, 1H),
47
7.55 (br, d, J = 7.99 Hz, 1H), 7.26 (t, J = 7.87 Hz, 1H), 4.58-4.50 (m, 1H), 4.32-4.23 (m, 1H),
3.49-3.39 (m, 1H), 3.39-3.36 (s, 3H), 2.75 (s, 3H), 2.62 (s, 3H), 2.45-2.31 (m, 1H), 2.16-2.03 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 170.1, 153.6, 144.6, 133.7, 133.5, 130.6, 130.1, 126.3,
122.7, 59.9, 44.6, 36.9, 36.7, 35.8, 30.2.
6.2.9 Synthesis of 4-(3-bromophenyl)-N-isopropyl-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (6.16):
The title compound 6.16 was prepared in accordance with the general procedure using N-
isopropylacrylamide as the dipolarophile. The product was purified by column chromatography
(1:1 ethyl acetate/dichloromethane) to afford 6.16 as a yellow solid (65 mg, 47 %). 1H NMR
(400 MHz, CDCl3) δ 7.78 (br, t, J = 1.78 Hz, 1H), 7.59-7.56 (m, 1H), 7.56-7.54 (m, 1H), 7.27 (t,
J = 7.87 Hz, 1H), 5.92 (br, s, 1H), 4.08-3.98 (m, 2H), 3.94-3.82 (m, 1H), 3.58-3.45 (m, 1H), 3.31
(s, 3H), 2.35-2.24 (m, 1H), 2.24-2.13 (m, 1H), 1.05 (d, J = 6.57 Hz, 3H), 0.90 (d, J = 6.57 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 153.5, 145.1, 133.5, 133.1, 130.4, 130.1, 126.1,
122.6, 64.3, 44.8, 41.5, 36.8, 29.8, 22.2.
6.2.10 Synthesis of N-benzyl-4-(3-bromophenyl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (6.17):
To a round bottom flask equipped with a vigreux condenser was added 6.13 (100 mg,
0.27 mmol, 1 equiv) and NEAT benzylamine (3.4 mL, 2.70 mmol, 10 equiv). The reaction
mixture was refluxed at 71 °C with stirring overnight. The product was purified by column
chromatography (95:5 ethyl acetate/dichloromethane) to afford 6.17 as a yellow solid (42 mg, 35
48
%). 1H NMR (400 MHz, CDCl3) δ 7.72 (t, J = 1.81 Hz, 1H), 7.58-7.54 (m, 1H), 7.44 (dt, J =
1.33 Hz, J = 7.88 Hz, 1H), 7.33-7.29 (m, 3H), 7.21 (t, J = 7.94 Hz, 1H), 7.09 (dd, J = 1.93 Hz, J
= 7.57 Hz, 2H), 6.04 (br, t, J = 5.26 Hz, 1H), 4.36 (dd, J = 6.00 Hz, J = 14.74 Hz, 1H), 4.27 (dd,
J = 5.66 Hz, J = 14.56 Hz, 1H), 4.10 (t, J = 6.39 Hz, 1H), 4.01-3.92 (m, 1H), 3.70-3.62 (m, 1H),
3.31 (s, 3H), 2.35-2.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 169.6, 153.6, 145.2, 137.2,
133.7, 133.0, 130.5, 130.4, 128.9, 127.9, 127.8, 126.1, 123.0, 64.3, 44.8, 43.7, 36.9, 30.0.
6.2.11 Synthesis of 1-(2-(3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazol-5-yl)ethyl)-3-
phenylurea (6.18):
To a round bottom flask equipped with a vigreux condenser was added 6.13 (60 mg, 0.16
mmol, 1 equiv), potassium carbonate (55 mg, 0.40 mmol, 2.5 equiv), and a minimal volume of
aniline for solvation. The reaction mixture was heated at 150 °C with stirring until all of 6.13 had
reacted. To the reaction mixture was added 1M HCl (equal volume to aniline) and the crude
product was extracted with ethyl acetate (3 x 5 mL). The organic layers were combined and dried
over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product
was purified by column chromatography (95:5 ethyl acetate/methanol) to afford 6.18 as a brown
solid (2 mg, 3 %). 1H NMR (400 MHz, CDCl3) δ 8.12 (br, t, J = 1.69 Hz, 1H), 7.86 (d, J = 7.86
Hz, 1H), 7.49 (br, d, J = 7.90 Hz, 1H), 7.29-7.20 (m, 5H), 7.10-7.04 (m, 1H), 6.73 (s, 1H), 5.96
(t, J = 5.88 Hz, 1H), 3.83 (s, 3H), 3.75 (q, J = 5.93 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
159.3, 155.9, 155.0, 138.2, 132.9, 132.0, 130.1, 129.4, 129.1, 124.6, 124.3, 122.7, 121.5, 37.4,
35.2, 26.4; HRMS (ESI) m/z [M + H]+ calcd for 400.0767, found 400.0761.
49
6.2.12 Synthesis of methyl (2-(3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazol-5-
yl)ethyl)carbamate (6.19):
To a round bottom flask was added 6.13 (100 mg, 0.27 mmol, 1 equiv), potassium tert-
butoxide (50 mg, 0.41 mmol, 1.5 equiv), and a minimal volume of THF for solvation. The
reaction mixture was stirred at room temperature for 1-2 h after which it was concentrated under
reduced pressure. The product was purified by column chromatography (95:5 ethyl
acetate/methanol) to afford 6.19 as a pale yellow solid (11 mg, 12 %). 1H NMR (400 MHz,
CDCl3) δ 8.21 (br, t, J = 1.86 Hz, 1H), 7.97 (d, J = 7.86 Hz, 1H), 7.50 (d, J = 8.02 Hz, 1H), 7.29
(t, J = 7.92 Hz, 1H), 5.59 (br, s, 1H), 3.85 (s, 3H), 3.74-3.64 (m, 5H), 2.97 (t, J = 6.25 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.5, 156.0, 154.6, 132.0, 130.1, 129.1, 128.5, 124.7, 123.2,
52.2, 38.3, 35.2, 26.3.
6.2.13 General procedure for Suzuki cross-coupling reactions:
To a Biotage microwave vial was added the cycloadduct (50 mg, 1 equiv), arylboronic
acid (1.1 equiv), tetrakis(triphenylphosphine)palladium(0) (0.05 equiv), and potassium carbonate
(2.5 equiv) in DMF. Approximately 1.5 mL of DMF was used for every 50 mg of the
cycloadduct. The vial was sealed with a cap and purged with nitrogen for ten minutes. The
reaction mixture was heated to 170 °C in a microwave for 22 minutes and then cooled to room
temperature. The contents from of the vial along with water (10x the volume of DMF used) were
added to a separatory funnel. The solution was extracted with ethyl acetate ten times. The
combined organic layers was dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by silica gel column chromatography.
50
6.2.14 Synthesis of methyl 4-([1,1’-biphenyl]-3-yl)-2-methyl-1-oxo-2,6,7,8-tetrahydro-1H-
pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (6.20):
The title compound 6.20 was prepared in accordance with the general procedure using
phenylboronic acid as the coupling agent. The product was purified by column chromatography
(3:2 ethyl acetate/hexane) to afford 6.20 as a pale yellow solid (19 mg, 38 %). 1H NMR (400
MHz, CDCl3) δ 7.86 (t, J = 1.85 Hz, 1H), 7.69-7.65 (m, 1H), 7.65-7.61 (m, 2H), 7.50-7.43 (m,
3H), 4.26 (dd, 1H), 3.56-3.51 (m, 4H), 3.38 (s, 3H), 2.49-2.39 (m, 1H), 2.29-2.20 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 171.3, 154.3, 146.0, 141.8, 140.3, 131.6, 129.6, 129.2, 128.8, 127.7,
127.2, 126.5, 126.3, 62.2, 52.4, 44.2, 36.9, 29.8.
6.2.15 Synthesis of methyl 4-(4’-carbamoyl-[1,1’-biphenyl]-3-yl)-2-methyl-1-oxo-2,6,7,8-
tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (6.21):
The title compound 6.21 was prepared in accordance with the general procedure using 4-
aminocarbonylphenylboronic acid as the coupling agent. The product was purified by column
chromatography (95:5 ethyl acetate/methanol) to afford 6.21 as a yellow solid (22 mg, 40 %). 1H
NMR (400 MHz, CDCl3) δ 7.94-7.88 (m, 3H), 7.71-7.67 (m, 3H), 7.50 (t, J = 7.62 Hz, 1H),
7.36-7.30 (m, 1H), 6.19 (br, s, 1H), 5.85 (br, s, 1H), 4.26 (dd, J = 3.86 Hz, J = 9.10 Hz, 1H),
4.23-4.14 (m, 1H), 3.60-3.51 (m, 4H), 3.39 (s, 3H), 2.51-2.40 (m, 1H), 2.30-2.21 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 171.3, 168.9, 154.3, 145.8, 143.9, 140.6, 132.4, 131.8, 129.6, 129.4,
128.0, 127.4, 127.2, 126.3, 62.3, 52.4, 44.3, 36.9, 29.8.
51
6.2.16 Synthesis of methyl 4-(4’-carbamoyl-[1,1’-biphenyl]-3-yl)-2,6-dimethyl-1-oxo-
2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxylate (6.22):
The title compound 6.22 was prepared in accordance with the general procedure using 4-
aminocarbonylphenylboronic acid as the coupling agent. The product was purified by column
chromatography (95:5 ethyl acetate/methanol) to afford 6.22 as an orange-yellow solid (18 mg,
31 %). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.35 Hz, 2H), 7.89 (br, t, J = 1.77 Hz, 1H),
7.70-7.66 (m, 3H), 7.55 (t, J = 7.30 Hz, 1H), 7.50-7.44 (m, 1H), 6.47 (br, s, 1H), 6.01 (br, s, 1H),
4.00-3.90 (m, 1H), 3.90-3.81 (m, 1H), 3.54 (s, 3H), 3.37 (s, 3H), 2.60-2.49 (m, 1H), 2.00-1.89
(m, 2H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 169.0, 155.6, 146.6, 143.7, 140.1,
132.1, 132.0, 129.5, 129.0, 128.6, 128.4, 128.1, 128.0, 127.3, 127.2, 70.1, 52.6, 44.4, 38.8, 37.1,
23.6.
6.2.17 Synthesis of N-benzyl-4-(4’-carbamoyl-[1,1’-biphenyl]-3-yl)-2-methyl-1-oxo-2,6,7,8-
tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazine-6-carboxamide (6.23):
The title compound 6.23 was prepared in accordance with the general procedure using 4-
aminocarbonylphenylboronic acid as the coupling agent. The product was purified by column
chromatography (95:5 ethyl acetate/methanol) to afford 6.23 as a yellow solid (20 mg, 30 %). 1H
NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.25 Hz, 2H), 7.79 (br, t, J = 1.69 Hz, 1H), 7.68 (dt, J =
1.51 Hz, J = 7.78 Hz, 1H), 7.63 (d, J = 8.28 Hz, 2H), 7.53 (dt, J = 1.44 Hz, J = 7.84 Hz, 1H),
7.45 (t, J = 7.75 Hz, 1H), 7.25-7.21 (m, 3H), 7.07-7.01 (m, 2H), 6.33 (t, J = 5.84 Hz, 1H), 6.20
52
(br, s, 1H), 5.72 (br, s, 1H), 4.34 (dd, J = 6.03 Hz, J = 14.70 Hz, 1H), 4.29-4.17 (m, 2H), 3.93-
3.81 (m, 1H), 3.80-3.72 (m, 1H), 3.33 (s, 3H), 2.38-2.27 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
169.8, 168.7, 153.7, 146.7, 143.6, 140.7, 137.2, 132.4, 131.6, 129.51, 129.48, 128.8, 128.0,
127.8, 127.7, 127.3, 127.2, 126.5, 64.2, 44.8, 43.7, 36.8, 29.9.
6.3 Results and Discussion
DOS was primarily employed to construct a library of structurally complex and diverse
verdazyl-derived compounds in an attempt to study the synthetic versatility of verdazyl radicals
as organic substrates to provide unique heterocyclic compounds. Based on the proposed DOS
strategy outlined in Scheme 6-1, 11 compounds were synthesized over a span of one month
(Scheme 6-2). Not all of the proposed molecules were synthesized as a result of time constraints.
Starting from the 1,5-dimethyl-3-(3-bromophenyl)-6-oxoverdazyl radical, 6.1, four
separate 1,3-DC reactions were carried out using methyl acrylate, methyl methacrylate, N,N-
dimethylacrylamide, and N-isopropylacrylamide to produce 6.13, 6.14, 6.15, and 6.16,
respectively. Verdazyl radical 6.1 was intentionally synthesized with an aryl bromide
functionality to enable Suzuki cross-coupling reactions to be performed on the cycloadducts
(6.13, 6.14, 6.15, and 6.16). However, only 6.13 and 6.14 were carried forward to the Suzuki
coupling reactions. Using 4-aminocarbonylphenylboronic acid as the coupling agent led to the
formation of 6.21 and 6.22 from 6.13 and 6.14, respectively. Compound 6.13 also underwent the
following reactions: a Suzuki coupling reaction with phenylboronic acid to yield 6.20, an
amidation reaction with benzylamine to give 6.17, a potassium tert-butoxide-mediated
rearrangement to afford the triazole 6.19, and an aniline-mediated rearrangement to produce a
the urea-containing triazole 6.18. The newly formed 6.17 was also converted to 6.23 via a Suzuki
coupling reaction with 4-aminocarbonylphenylboronic acid.
53
Scheme 6-2. Synthesized verdazyl-derived compounds.
N
N N
N
O
COOMe
Br
N
N N
N
O
Br
6.1
6.13
N
N N
N
O
Br
COOMe
6.14
N
N N
N
O
Br
CON(CH3)2
6.15
N
N N
N
O
Br
CONHCH(CH3)2
6.16
N
N N
N
O
CONHCH2Ph
Br
6.17
N
NN
NH
O
HN
Br
6.18
N
NN
NH
O
Br
MeO6.19
N
N N
N
O
COOMe
6.20
N
N N
N
O
COOMe
O
NH2
6.21
N
N N
N
O
COOMe
O
NH26.22
N
N N
N
O
CONHCH2Ph
O
NH2
6.23
1,3-DC
1,3-DC1,3-DC
1,3-DC
Suzuki
Suzuki
Amidation
Suzuki
Suzuki
Base
Rearrange.
Nucleophilic
Rearrange.
It was interesting to observe that the potassium tert-butoxide-induced rearrangement of
6.13 did not lead to the formation of the anticipated pyrazolotriazinone, but to the formation of a
triazole 6.19. This result was not consistent with earlier studies done by our lab where
54
pyrazolotetrazinanones were shown to rearrange in the presence of base to give
pyrazolotriazinones and in the presence of a nucleophilic base to give triazoles (Scheme 5-3).2 If
the potassium tert-butoxide did indeed behave as a nucleophile rather than a base, a tert-butyl
carbamate-containing product, 6.24 (Figure 6-1), should have formed instead of the methyl
carbamate-containing 6.19 if the proposed mechanism (Scheme 5-5) is valid. The formation of
6.19 suggests that the proposed mechanism for the preparation of triazoles from
pyrazolotetrazinanones is inaccurate (Scheme 5-5). It is possible that nucleophiles do not
actually become incorporated into the carbamate moiety of the triazole as suggested earlier but
instead become incorporated via an esterification reaction after the triazole is formed. If this is
the case, 6.24 should form in low to no yields from the intermediate 6.19 due to the weak
nucleophilic nature of potassium tert-butoxide to participate in the esterification reaction. The
absence of 6.24 in the reaction mixture supports this newly proposed mechanism, however, the
mechanism is purely speculative and does not provide a full account of how the triazole was
prepared. Further studies into elucidating the mechanism will be the subject of future
investigation.
Figure 6-1. Structure of a tert-butyl carbamate-containing triazole (6.24).
The preparation of 6.18 from 6.13 using aniline in the presence of potassium carbonate at
150 °C marked another intriguing reaction. In an attempt to convert the ester of 6.13 to an amide
using aniline, a urea-containing triazole 6.18 was formed. Two possible pathways could lead to
6.18 (Scheme 6-3). One pathway involves an anticipated amidation reaction to form 6.25, which
would react with the excess nucleophilic aniline to rearrange to 6.18 via the intermediacy of
6.26. The other possible mode involves an aniline-mediated rearrangement to form the
pyrazolotriazinone intermediate 6.27, which subsequently rearranges in the presence of the
excess aniline to the urea-containing triazole 6.18.
55
Scheme 6-3. Proposed pathways for the formation of 6.18.
N
N
N NH
O
6.18
Br
N
N N
N
O
COOMe
Br
NH
6.13
N
N N
N
O
CONHPh
Br6.25 NH2
N
N N
O
NH
Br6.27
COOMe
NH2 NH2
N
N N
O
NH
Br6.26
CONHPh
NH2
NH2
Although the synthetic objective of the DOS approach was not fully realized as only a
small number of structurally complex and diverse verdazyl-derived compounds were made, we
were successful in initiating the DOS application, demonstrating to an extent the compatibility of
DOS to this system as well as the synthetic flexibility of verdazyl radicals as organic substrates.
Further pursuit of the synthetic goal would involve subjecting 6.13 and 6.14 to a range of amines
in order to convert them to the amide derivatives, which then needs to react with a variety of
arylboronic acids in a Suzuki coupling reaction along with the compounds, 6.13-6.17. The
resulting Suzuki products other than the 6.14-derived products, which cannot rearrange due to
the absence of an α-hydrogen, are required to rearrange to the pyrazolotriazinones and triazoles,
despite the unanticipated formation of 6.19 from 6.13 in the presence of potassium tert-butoxide.
The 11 synthesized compounds was pooled with 75 other verdazyl-derived compounds
prepared by our lab and subsequently screened for their ability to decrease the viability of acute
myeloid leukemia and multiple myeloma cell lines. Of the 86 compounds tested, two
compounds, neither of which were part of the 11-membered library, exhibited potential
biological activity. One of these lead compounds, 6.28, was shown to be the most promising as it
was able to kill the two cell lines at concentrations of 5000 and 500 µM. The other lead
compound, 6.29, killed the two cell lines at the higher concentration of 5000 µM. The required
concentrations of 6.28 and 6.29 needed to decrease the cancer cells’ viability were too high,
making them non-ideal therapeutic drugs. Nevertheless, the results were encouraging because
56
these early hit structures can be optimized by synthesizing a library of structurally similar
analogs based on the structural platforms of 6.28 and 6.29. Since DOS is not specifically directed
at a selected target,3-4 the possibility of finding lead compounds with drug-like properties can be
improved by conducting further screening experiments against a multitude of cell lines and by
additionally preparing more verdazyl-derived heterocycles.
Figure 6-2. Structures of the two lead compounds, 6.28 and 6.29.
6.4 Concluding Remarks
The recent development of verdazyl radicals as novel substrates for heterocyclic
syntheses has served as an important engine for driving the present DOS study. The aim of the
investigation was to construct a library of structurally complex and diverse verdazyl-derived
heterocycles in order to assess the synthetic utility of verdazyl radicals as precursors to unique
heterocycles, to evaluate the practicability of DOS to this system, and to screen the library of
compounds for their biological activity against two cancer cell lines. Attempted syntheses of the
proposed DOS library (Scheme 6-1) resulted in 11 compounds (Scheme 6-2), where the
preparation of the triazole 6.18 and 6.19 were particularly interesting. Despite the fact that the
synthetic objective was not fully fulfilled, the initial progress of the DOS approach demonstrated
to some degree the synthetic versatility of verdazyl radicals as organic starting materials and the
feasibility of the DOS application. The biological activity testing involved screening the 11
compounds in addition to the 75 compounds made by our lab for their ability to kill acute
myeloid leukemia and multiple myeloma cells at concentrations of 5000 and 500 µM. A hit was
not generated by any of the 11 synthesized compounds, however, compound 6.32 and 6.33
showed encouraging results worthy of future endeavors.
6.5 Future Work
The theme in DOS is to build a very large library of structurally complex and diverse
small molecules and then screen these compounds for their biological activity against as many
targets as possible. This approach increases the likelihood of finding small molecule probes to
57
explore biological processes and to unveil possible drug candidates.3-4 Adopting this DOS theme
for verdazyl-derived heterocycles, requires to first synthesize the necessary compounds needed
to complete the library as discussed earlier. The library can be further expanded, after a sequence
of amidations (if necessary), Suzuki couplings, and rearrangement reactions, by using other
acrylate and acrylamide dipolarophiles for the 1,3-DC reaction with 6.1.
It would be interesting to employ appendage diversity-generating process, at the
condensation reaction between 1.7a and a variety of bromine-containing aldehydes, to eventually
produce a novel collection of structurally diverse verdazyl radicals 6.30 (Scheme 6-4).
Subjecting these newly formed verdazyl radicals to the same sequence of reactions as outlined in
Scheme 6-1, would result in a stupendous-sized library of these verdazyl-originated compounds.
Scheme 6-4. Appendage diversification towards the synthesis of verdazyl radicals.
O
NN
NH2 NH2
N
HN NH
N
O
Ar
BrBr
Br
Br
N
N N
N
O
Ar
[ox]
O
H
=
(ortho, para)
1.7a
Ar
Ar
(ortho', meta', para')
(ortho', meta', para')Br
6.30
The mechanism behind the formation of 6.18 and 6.19 from 6.13 should be considerably
investigated. It would be interesting to see if similar products, a urea-containing triazole and a
methyl carbamate-containing triazole, would form if compounds 6.15-6.17 were treated under
the same set of reaction conditions and reagents as those used in the formation of 6.18 and 6.19.
An attempt to isolate an intermediate in the synthesis of 6.18 is worthwhile as mechanistic
insights can be deduced relating to whether one of the proposed pathways (Scheme 6-3) is likely
to occur or whether another pathway is operating. Potassium tert-butoxide was shown to induce
the rearrangement of 6.13 to a methyl carbamate-containing 6.19. It would be insightful to
employ other bases with weak nucleophilic properties in an attempt to replicate this result and
make justifiable remarks on the validity of the proposed mechanism for the formation of triazoles
from the pyrazolotetrazinanones (Scheme 5-5).
58
6.6 References (1) Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org.
Chem. 2008, 4571-4574. (2) Chen, E. K. Y.; Bancerz, M.; Georges, M. K. Publication in Progress. (3) Schreiber, S. L. Science 2000, 287, 1964-1969. (4) Tan, D. S. Nature Chem. Bio. 2005, 1, 74-84.
59
7. Verdazyl Radicals as Precursors to Heteraphanes 7.1 Introduction and Objective
In an aim to pioneer the chemistry of verdazyl radicals as novel organic substrates, our
laboratory has begun to study the scope of the different types of molecular scaffolds that are
possible beginning with verdazyl radicals. A summary of what has been accomplished to date is
provided in (Figure 7-1).1,2
Figure 7-1. General products formed from the verdazyl radical precursor.
In one particular venture, the [3.3]metacyclophane, 7.2, was serendipitously synthesized
from the 1,5-dimethyl-3-(3-vinylphenyl)-6-oxoverdazyl radical precursor, 7.1 (Scheme 7-1)
while attempting to use the verdazyl radical to prepare novel polymeric structures, such as 7.3. In
the end macrostructure 7.3 did indeed form but the heteraphane 7.2 precipitated out of the
reaction mixture in about 10 % yield. It was proposed that 7.2 originated from two intermediate
azomethine imines derived from 7.1, and their subsequent stepwise inter-intramolecular double
60
1,3-DC reactions with each other.3 The synthesis of 7.2 marked the first verdazyl-derived
heteraphane, sparking a movement in our lab to pursue other bridged aromatic systems derived
from these stable radicals.
Scheme 7-1. Attempted synthesis of the linear polyverdazyl macrostructure 7.3.
In the last few decades, bridged aromatic compounds known as phanes have attracted
considerable attention due to their synthetic challenges, structural properties, conformational
behaviours, and their host-guest binding chemistry.4 Phanes incorporating at least a single
bridged biphenyl unit in their molecular structure are called biphenylophanes and only a small
number of these structures have been synthesized compared to their cyclophane counterparts.5
Even rarer are biphenylophanes with two biphenyl moieties arranged in a π-stacked orientation –
face-to-face, edge-to-face, or slip stacked.
In an attempt to assess the versatility and limitations of verdazyl radicals as substrates in
organic synthesis, and in this particular case their use as substrates for the synthesis of unique
phanes, a study was initiated to prepare a verdazyl-derived biphenylophane with two biphenyl-
stacked units. In addition to expanding both the libraries of verdazyl-derived heterocycles and
verdazyl-derived phanes, the investigation was also fueled by the scarcity of biphenyl-stacked
biphenylophanes and their resulting structural and conformational analysis. Herein, we describe
the synthetic strategy to both the [3.3](3,4’,3,4’)biphenylophane, 7.7, and its 1,5-dimethyl-3-
(4’vinylbiphenyl-3-yl)-6-oxoverdazyl radical precursor, 7.6, and examine the structural and
conformational features of 7.7 using 1H NMR, VT NMR, and X-ray diffraction studies.
61
7.2 Experimental Section
7.2.1 Materials and Equipment
Chemicals. All reagents and ACS grade solvents were purchased from Sigma-Aldrich or
VWR unless otherwise stated. Column chromatography was performed with Silica Gel P60
(mesh size 40-63 µm) obtained from Silicycle. Thin layer chromatography (TLC) was performed
on aluminum plates coated with silica (pore size of 60Å) and fluorescent indicator, obtained
from EMD Chemicals, and visualized under UV (254 nm) light.
General. NMR spectra were acquired on a Bruker Avance III spectrometer at 23 °C,
operating at 400 MHz for 1H NMR and 100 MHz for 13C NMR or a Varian Unity INOVA-500
spectrometer at variable temperatures as stated, operating at 500 MHz for 1H NMR and 125 MHz
for 13C NMR. Chemical shifts (δ) are reported in parts per million (ppm) relative to
tetramethylsilane (0 ppm) or CD2Cl2 (5.32 ppm) for 1H NMR spectra and CDCl3 (77.0 ppm) for 13C NMR. Coupling constants (J) are reported in hertz (Hz). Spin multiplicities are designated by
the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br
(broad). Accurate mass determinations (HRMS) were carried out by the AIMS lab, Department
of Chemistry, University of Toronto using either a Waters GC TOF mass spectrometer with an
EI source and accurate mass capability or an AB/Sciex QStar mass spectrometer with an ESI
source, MS/MS and accurate mass capabilities, associated with an Agilent 1100 capillary LC
system. The single crystal X-ray structural determination was carried out at the X-ray facility,
Department of Chemistry, University of Toronto on a Bruker-Nonius Kappa-CCD diffractometer
using monochromated Mo-Kα radiation and were measured using a combination of φ scans and
ω scans with κ offsets, to fill the Ewald sphere. The data were processed using the Denzo-SMN
package.6 Absorption corrections were carried out using SORTAV.7 The structure was solved
and refined using SHELXTL V6.18 for full-matrix least-squares refinement that was based on F2.
All hydrogen atoms were included in calculated positions and allowed to refine in riding-motion
approximation with U~iso~ tied to the carrier atom. Microwave irradiation was carried out in a
Biotage Initiator 2.5 in a sealed microwave vial.
62
7.2.2 Synthesis of 4’-vinylbiphenyl-3-carbaldehyde (7.4):
To a Biotage microwave vial was added 3-bromobenzaldehyde (0.50 g, 2.7 mmol, 1
equiv), 4-vinylphenylboronic acid (0.44 g, 3.0 mmol, 1.1 equiv),
tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol, 0.05 equiv), and potassium
carbonate (0.93 g, 6.8 mmol, 2.5 equiv) in DMF (15 mL). The vial was sealed with a cap and
purged with nitrogen for ten minutes. The reaction mixture was heated to 170 °C in a microwave
for 22 minutes and was then cooled to room temperature. The contents from the vial and water
(150 mL) were added to a separatory funnel and the solution was extracted with ethyl acetate (10
x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure to give a black viscous liquid. The crude product was
purified by column chromatography (silica, dichloromethane/hexane 3:2) to afford 7.4 (0.2533 -
0.3095 g, 45-55 %) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.09 (br, t, J
= 1.71 Hz, 1H), 7.86-7.82 (m, 2H), 7.61-7.56 (m, 3H), 7.52-7.48 (m, 2H), 6.77 (dd, J = 10.9 Hz,
J = 17.6 Hz, 1H), 5.81 (d, J = 17.7 Hz, 1H), 5.30 (d, J = 10.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 192.2, 141.5, 138.8, 137.2, 136.8, 136.1, 132.7, 129.4, 128.6, 127.8, 127.1, 126.8,
114.4; HRMS (EI) m/z [M]+ calcd for 208.0888, found 208.0884.
7.2.3 Synthesis of 1,5-dimethyl-3-(4’-vinylbiphenyl-3-yl)-1,2,4,5-tetrazinan-6-one (7.5):
To a round bottom flask equipped with an addition funnel was added 1.7a (0.10 g, 0.85
mmol, 1.1 equiv) in toluene (3 mL). Compound 1.7a was forced into solution using heat and
vigorous shaking. The reaction flask was immersed into an oil bath where the oil bath was heated
to 85 °C with both the oil bath and the reaction mixture stirring. A solution of 7.4 (0.16 g, 0.76
mmol, 1 equiv) in toluene (4 mL), which was also forced to dissolve using heat and vigorous
shaking, was added drop wise every five seconds via the addition funnel. The reaction was
monitored by TLC (silica, ethyl acetate/methanol 95:5) and removed from the heat when nearly
63
all of 7.4 had reacted. The reaction mixture was concentrated under reduced pressure to give an
orange-yellow solid. The crude product was purified by column chromatography (silica, ethyl
acetate/methanol 95:5) to give 7.5 (97 - 120 mg, 37-45 %) as an off-white solid. 1H NMR (400
MHz, CDCl3) δ 7.77 (br, t, J =1.86 Hz, 1H), 7.60-7.45 (m, 8H), 6.77 (dd, J = 10.9 Hz, J = 17.8
Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 10.9 Hz, 1H), 5.12 (t, J = 9.7 Hz, 1H), 4.43 (d, J
= 9.7 Hz, 2H), 3.18 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 155.3, 141.1, 139.9, 136.8, 136.1,
135.6, 129.0, 127.2, 127.1, 126.6, 125.2, 125.1, 114.0, 69.2, 38.0; HRMS (ESI) m/z [M + H]+
calcd for 309.1709, found 309.1720.
7.2.4 Synthesis of 1,5-dimethyl-3-(4’-vinylbiphenyl-3-yl)-6-oxoverdazyl radical (7.6):
To a solution of 7.5 (0.40 g, 1.3 mmol, 1 equiv) in ethyl acetate (200 mL) was added a
saturated solution of sodium (meta)periodate (0.69 g, 3.2 mmol, 2.5 equiv) in water. The
biphasic system was allowed to stir during which time a noticeable color change of the organic
layer to red was observed. The reaction was monitored by TLC (silica, ethyl acetate/methanol
95:5) until all of 7.5 had reacted. The aqueous layer was removed and extracted with ethyl
acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure to afford crude 7.6 (0.32 - 0.34 g, 80-85 %) as
a red solid.
7.2.5 Synthesis of [3.3](3,4’,3,4’)biphenylophane (7.7):
64
To a reaction flask was added crude 7.6 (50 mg, 0.16 mmol) in dichloromethane (2 mL).
The flask was sealed and left to stir for 5-7 days. The reaction was monitored by TLC (silica,
ethyl acetate/dichloromethane 3:2) until 7.6 had fully reacted. The reaction mixture was
concentrated under reduced pressure to give an orange-yellow solid. The crude product was
purified by column chromatography (silica, ethyl acetate/dichloromethane 3:2) to afford the title
compound 7.7 (0.5-1.0 mg, 1-2 %) as an off-white solid. Recrystallization of 7.7 via a slow
evaporation of their solution in DCM gave single crystals. 1H NMR (400 MHz, CDCl3) δ 7.64
(dt, J = 1.65 Hz, J = 7.37 Hz, 1H), 7.51 (dd, J = 1.82 Hz, J = 8.28 Hz, 1H), 7.39-7.29 (m, 3H),
6.82 (dd, J = 1.86 Hz, J = 7.87 Hz, 1H), 6.80 ( br, t, J = 1.81 Hz, 1H), 6.39 (dd, J = 1.89 Hz, 7.85
Hz, 1H), 4.55-4.48 (m, 1H), 4.42-4.34 (m, 1H), 3.83-3.73 (m, 1H), 3.43 (s, 3H), 2.58-2.44 (m,
1H), 2.21-2.10 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.4, 148.8, 140.9, 139.5, 139.3, 131.7,
129.4, 128.54, 128.47, 128.0, 127.3, 126.8, 126.3, 126.1, 67.0, 46.2, 37.2, 34.7; HRMS (ESI) m/z
[M + H]+ calcd for 609.2720, found 609.2719.
7.2.6 Synthesis of N,1-dimethyl-2-((4’-(2-methyl-1-oxo-4-(4’-vinyl-[1,1’-biphenyl]-3-yl)-
2,6,7,8-tetrahydro-1H-pyrazolo[1,2-a][1,2,4,5]tetrazin-6-yl)-[1,1’-biphenyl]-3-
yl)methylene)hydrazinecarboxamide (7.8):
The title compound 7.8 was formed along side 7.7. It was produced in 9-11 % yield as a
yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.65-7.61 (m, 1H), 7.57-7.52 (m, 2H),
7.50-7.45 (m, 2H), 7.45-7.39 (m, 4H), 7.38-7.32 (m, 5H), 7.05 (d, J = 8.22 Hz, 2H), 6.68 (dd, J =
10.84 Hz, J = 17.79 Hz, 1H), 6.52 (br, s, 1H), 5.72 (d, J = 17.71 Hz, 1H), 5.25 (d, J = 10.92 Hz,
1H), 4.82-4.75 (m, 1H), 4.36-4.27 (m, 1H), 3.80-3.70 (m, 1H), 3.39 (s, 3H), 3.28 (s, 3H), 2.93 (d,
J = 4.89 Hz, 3H), 2.67-2.53 (m, 1H), 2.29-2.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.4,
154.9, 147.6, 140.9, 140.8, 140.2, 139.6, 139.3, 136.8, 136.2, 135.8, 135.4, 132.3, 129.2, 128.8,
127.9, 127.12, 127.08, 126.6, 126.4, 125.5, 125.4, 114.1, 66.3, 45.1, 36.8, 33.8, 29.7, 28.4, 27.2,
22.7, 14.2; HRMS (ESI) m/z [M + H]+ calcd for 598.2925, found 598.2916.
65
7.2.7 Synthesis of N,1-dimethyl-2-((4’-vinyl-[1,1’-biphenyl]-3-yl)methylene)-
hydrazinecarboxamide (7.9):
The title compound 7.9 was formed along side 7.7. It was produced in 4-6 % yield as a
yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.65-7.54 (m, 5H), 7.54-7.43 (m, 3H),
6.77 (dd, J = 10.88 Hz, J = 17.90 Hz, 1H), 6.59 (br, s, 1H), 5.81 (d, J = 17.66 Hz, 1H), 5.29 (d, J
= 10.90 Hz, 1H), 3.39 (s, 3H), 2.95 (d, J = 4.87 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.4,
141.3, 140.0, 136.9, 136.2, 136.0, 135.4, 129.1, 127.8, 127.2, 126.7, 125.4, 125.2, 114.2, 28.3,
27.1; HRMS (ESI) m/z [M + H]+ calcd for 294.1600, found 294.1611.
7.3 Results and Discussion
In an effort to prepare a verdazyl-derived biphenyl-stacked biphenylophane, the
[3.3](3,4’,3,4’)biphenylophane (7.7) was marked as the synthetic target (Figure 7-2).
Retrosynthetic analysis revealed that the target 7.7 could be formed from a double 1,3-DC
reaction between two molecules of the verdazyl radical 7.6, which could readily be imagined to
be derived from the oxidation of 7.5. Further retrosynthetic analysis suggested that 7.5 could be
synthesized from the condensation reaction between 7.4 and 1.7a, where 7.4 could be produced
from a Suzuki cross-coupling reaction between 3-bromobenzaldehyde and 4-vinylphenylboronic
acid. The structure of 7.6 was specifically designed in a similar manner to 7.1, where a styrene
dipolarophile functionality was incorporated as part of the verdazyl structure. This structural
feature was essential to enable the verdazyl radical the bifunctional role of behaving as both a
1,3-dipole, via an intermediate azomethine imine, and a dipolarophile, via the styrene
functionality. It is worth noting that there are very few examples of phanes with bicyclic bridging
systems and that both 7.2 and 7.7 have this additional unique structural characteristic.
66
Figure 7-2. Retrosynthetic approach to the target biphenylophane 7.7.
With a synthetic pathway devised as dictated by the retrosynthetic analysis, 4’-
vinylbiphenyl-3-carbaldehyde, 7.4, was synthesized in 45-55 % yield by the microwave-assisted
Suzuki coupling reaction of 3-bromobenzaldehyde with 4-vinylphenylboronic acid in the
presence of tetrakis(triphenylphosphine)palladium(0) catalyst and potassium carbonate at 170 °C
(Scheme 7-2). Subsequent condensation of 7.4 with N,N’-dimethylcarbonohydrazide, 1.7a, at 85
°C was carried out to afford the 1,5-dimethyl-3-(4’-vinylbiphenyl-3-yl)-1,2,4,5-tetrazinan-6-one,
7.5, in 37-45 % yield. Intermediate 7.5 was oxidized to the corresponding 1,5-dimethyl-3-
(4’vinylbiphenyl-3-yl)-6-oxoverdazyl radical, 7.6, in 80-85 % crude yield with NaIO4. It should
be noting that the oxidation reaction was not clean as several side products were formed. In an
attempt to purify the verdazyl radical via column chromatography, a low yield was achieved. It
was speculated that some intermediate 7.6 reacted with each other in a 1,3-DC reaction to form
the mono-addition cycloadduct 7.12. Without wanting to disrupt the following intramolecular
cyclization reaction of 7.12 to form the target 7.7 and thus lower the yield of 7.7, 7.6 was left in
the crude form along with the side products.
Although 7.6 was not characterized due to its paramagnetic nature, inference on its
synthesis was made based on the formation of 7.7 since 1,3-DC reactions of numerous verdazyl
radicals have been previously carried out by our lab. The target biphenylophane 7.7 was
produced in 1-2 % from the 7.6 precursor. While this yield was disappointing, two points must
be kept in mind. First, the yield was calculated based on a crude verdazyl radical mixture and
second, some yields reported by other groups for the preparation of their biphenylophanes were
also low. For example, Stoddart et al reported a 2 % yield for the directed synthesis of
biphenylophane 4.9 (Scheme 4-1).9
67
Scheme 7-2. Synthetic route to biphenylophane 7.7.
In previous work done by our lab, we described the synthesis of unique
pyrazolotetrazinanone heterocycles from the corresponding verdazyl radicals. It was proposed
that these heterocyclic compounds originated from an intermediate azomethine imine and its
subsequent 1,3-DC reaction with various dipolarophiles (Scheme 5-2). In the present work where
the dipolarophile is incorporated in the verdazyl structure, we surmised that the mechanism for
the transformation from 7.6 to 7.7 proceeds by a tandem inter-intramolecular 1,3-DC process
rather than a concerted process (Scheme 7-3). Two verdazyl radicals, 7.6, react together through
a disproportionation-type hydrogen abstraction reaction to generate the leucoverdazyl, 7.10, and
the azomethine imine 7.11. In the presence of oxygen, 7.10 readily oxidizes to 7.6 while 7.11
reacts with the styrene functionality of 7.6 in an intermolecular 1,3-DC reaction to form the
verdazyl cycloadduct 7.12. By means of the same hydrogen abstraction process, 7.12 is
converted to the azomethine imine cycloadduct 7.13, which reacts intramolecularly through a
1,3-DC reaction to afford the biphenylophane 7.7. We speculate that the mechanism does not
proceed through two concerted intermolecular 1,3-DC reactions between two molecules of 7.11.
The reason for this is that the formation of 7.11 is suggested to be the rate-determining step.
Once it is generated in situ it reacts immediately, due to its reactive nature, with a nearby
dipolarophile. This nearby molecule is very likely the verdazyl radical 7.6 as opposed to the
68
azomethine imine 7.11. However in the rare case where two molecules of 7.11 are in close
proximity with each other, it is not likely for both of these molecules to approach each other with
the right orientation and undergo the two 1,3-DC reactions simultaneously to form 7.7.
Scheme 7-3. Proposed mechanism for the transformation from 7.6 to 7.7.
N
N N
N
O
CH2
7.10
7.11
N
N N
N
O
CH2
H H
N
N N
N
O
+N
N NH
N
O
+N
N N
N
O
N
N N
N
O
O2
7.6 7.6
N
N N
N
O
NN
NN
O
N
N N
N
O
NN
NN
O
7.6
Intermolecular 1,3-DC
Azomethine Imine
Formation via
H Abstraction
Intramolecular 1,3-DC
7.7
Concerted
Intermolecular
1,3-DC
7.12
7.13
N
N N
N
O
N
N N
N
O
7.11
Two semicarbazone compounds 7.8 and 7.9 were formed in 9-11 % and 4-6 % yield,
respectively, which were much larger than the 1-2 % yield obtained for 7.7. The structure of
these semicarbazones is unusual because of the missing nitrogen of the tetrazinanone backbone.
Possibly more intriguing is the fact that this phenomenon has been observed in 1,3-DC reactions
of other verdazyl radicals. In an effort to determine if these semicarbazones were decomposition
products of verdazyl radicals, a solution of 7.10 in DCM was allowed to stir at room temperature
for more than a week (Scheme 7-4). From the reaction mixture a product was isolated in 11 %
69
yield and characterized to be the semicarbazone 7.15. The formation of 7.15 signifies that
verdazyl radicals decompose to form semicarbazones, a finding that has not been reported in
literature. It is speculated that suppressing the formation of these semicarbazones would
ultimately result in an improvement in the yield of 7.7, as well as other pyrazolotetrazinanone
cycloadducts.
Scheme 7-4. Decomposition of 7.14 to 7.15.
A NMR study at 296 K was conducted on 7.7 to verify its structure and to also acquire
insights into its conformational and configurational properties (Figure 7-3). From the 1H NMR
spectrum, the chemical shift, multiplicity, and integration of the six aliphatic peaks are consistent
with the structure of the bicyclic bridging moieties. In the aromatic region, five distinct peaks
plus three additional overlapping peaks are shown. The fact that there are eight aromatic peaks
and six aliphatic peaks in the spectrum suggests that the structure is symmetric. This is also
supported by the 13C NMR data (Appendix 8.1), which shows 18 peaks for the 36 carbon-
containing biphenylophane 7.7. The multiplicity of the aromatic peaks (i.e. dd, dt, t) is indicative
of long range coupling. This is confirmed through a COSY 1H NMR experiment (Appendix 8.1),
which shows complex multiple coupling patterns indicative of restricted rotation of the biphenyl
units. This rigidifying property of the biphenyl moieties is supported by the fact that the
symmetric pair of the eight aromatic protons of each biphenyl unit are magnetically non-
equivalent (i.e. different chemical environments for all eight protons), as observed by the
presence of eight aromatic peaks. The relatively up-field shift of the three aromatic peaks at 6.82,
6.80, and 6.39 ppm insinuates that these protons are in the vicinity of a π-electron cloud
generated by the biphenyl units. This further suggests that 7.7 very likely adopted an “anti-
conformation,” where an anti-arrangement is assumed by the meta-linked phenyl rings.
70
Figure 7-3. 1H NMR spectrum of biphenylophane 7.7 at 296 K.
To furthermore examine the structural properties of 7.7, the crystal structure was
determined by a single crystal X-ray diffraction study conducted at 150 K (Appendix 8.2). The
molecular structure (Figure 7-4) reveals 7.7 to be symmetric and to assume an “anti-
conformation.” To illustrate the shielding effect experienced by certain aromatic protons as a
consequence of adopting an “anti-conformation,” six aromatic protons, three on each biphenyl
units, are found in the region over the π-electron cloud generated by the opposite biphenyl
system. Although X-ray crystallography involves studying a compound’s structure in the crystal
lattice form as opposed to a solution state form, these X-ray results coincide with those obtained
from the prior NMR study.
Both edge-to-face and slip stacking interactions are present between the two biphenyl
units, where the former interactions are found between the meta-linked phenyl of one biphenyl
unit and the para-linked phenyl of the second biphenyl unit while the latter interaction is found
between the two para-linked phenyls. Each of the four aromatic rings are found to adopt planar
geometries, which is unanticipated due to the severe steric bulk that is observed in the space-
filling model of 7.7 (Figure 7-5). The six pivot bonds (C1-C34, C5-C7, C11-C13, C16-C19,
C23-C25, C29-C31) are deviated to a small degree from the ideal 120° suggesting that the
developing ring strain, formed from the four phenyl rings as they assume their planar geometries,
71
becomes relieve by bending these six pivot bonds. While minimal strain is found for the biphenyl
units, bending and puckering are observed for the bicyclic bridging systems.
The biphenylophane structure have two chiral centers, denoted as C1 and C19, allowing
for four possible stereoisomers, 1R,19R, 1R,19S, 1S,19R, and 1S,19S. Due to the symmetry of
7.7, the 1R,19S and 1S,19R stereoisomers are superimposable. The molecular structure
illustrated that the isolated biphenylophane molecule was the (1S,19S)-stereoisomer. Further
studies into dissecting this reaction pathway and its kinetic or thermodynamic control will be the
focus of future investigation.
Figure 7-4. Molecular structure of 7.7 in two different views. Atom labels are shown in the bottom figure.
72
Figure 7-5. Space-filling model of 7.7.
Both X-ray diffraction and NMR studies suggest that 7.7 adopts the “anti-conformation.”
An attempt to detect the “syn-conformer” was made by employing VT 1H NMR. In addition to
exploring this conformational isomerization process, an interest was also taken to observe any
ring flipping processes in the bicyclic bridging systems. However, due to the rigidity of these
bicyclic bridging units a higher activation barrier than the anti↔syn equilibration process was
anticipated. The prior NMR study on 7.7 indicated that the “anti-conformer” was the only
conformer present in solution at 296 K while the X-ray study showed the same conformation, but
in the crystalline state, at 150 K. Although these results likely suggest that the “anti-conformer”
was the more stable conformer, a need to go to lower temperature was necessary to further
ensure that this property was held true by the “anti-conformer.” In the temperature range
between 243 K and 323 K, there are no major changes in the chemical shifts or multiplicities in
both the aliphatic and aromatic peaks. This observation suggests that the temperature was not
high enough to induce a change in either the conformational isomerization process or the ring
flipping of the bicyclic bridges; a need to go to higher temperature is required to overcome the
activation barrier of both conformational processes. The problem associated with high
temperature NMR is that many deuterated solvents with high boiling points are aromatic in
nature and as a consequence, their residual peaks could potentially overlap with 7.7’s aromatic
peaks. Utilizing deuterated solvents that are non-aromatic with a high boiling point such as d6-
DMSO or d7-DMF is also a problem because they do not dissolve 7.7. This issue has not been
addressed bringing a halt to exploring the conformational dynamics of 7.7.
7.4 Concluding Remarks
In an attempt to assess the synthetic utility of verdazyl radicals as substrates in
heterocyclic syntheses, coupled with the scarcity of biphenyl-stacked biphenylophanes, a study
was initiated to prepare a verdazyl-derived biphenylophane with two biphenyl-stacked units and
73
to subsequently investigate its structural and conformational characteristics. Herein, we have
reported the novel synthesis of the verdazyl-derived biphenyl-stacked
[3.3](3,4’,3,4’)biphenylophane 7.7, thus strengthening the versatility of these stable radicals as
precursors to heterocyclic syntheses. The approach was initiated by the microwave-assisted
Suzuki coupling between 4-vinylphenylboronic acid and 3-bromobenzaldehyde to construct 4’-
vinylbiphenyl-3-carbaldehyde. The subsequent condensation with N,N’-
dimethylcarbonohydrazide produced 1,5-dimethyl-3-(4’-vinylbiphenyl-3-yl)-1,2,4,5-tetrazinan-
6-one, which in the presence of sodium (meta)periodate oxidized to 1,5-dimethyl-3-(4’-
vinylbiphenyl-3-yl)-6-oxoverdazyl radical (7.6). Upon a double 1,3-DC reaction, 7.6 was
transformed to the target biphenylophane 7.7. It was proposed that the formation of 7.7
originated from two intermediate azomethine imines derived from 7.6, and their subsequent
tandem inter-intramolecular double 1,3-DC reaction with each other.
NMR studies at 296 K showed 7.7 to be a symmetric molecule with restricted biphenyl
units, where the two meta-linked phenyl rings were arranged in an anti-fashion. X-ray diffraction
studies confirmed the symmetry and “anti-conformation” of 7.7 and revealed the presence of π-
stacking interactions between the biphenyl units. X-ray diffraction studies also indicated that the
isolated 7.7 was the (S,S)-stereoisomer. The conformational behaviour of 7.7 was explored, via
VT 1H NMR, in an aim to detect the “syn-conformer” and also to observe any ring flipping
process in the bicyclic bridging systems. However, NMR experiments carried out at temperature
up to 323 K indicated that these conformational processes were immobile and that higher
temperatures were required to overcome these energy barriers.
7.5 Future Work
The present investigation demonstrated that verdazyl radicals can be employed as starting
materials to synthesize biphenylophanes. This outcome will surely stimulate future research into
designing other verdazyl-derived heteraphanes in a large effort to expand the library of verdazyl-
derived compounds, particularly verdazyl-derived bridged aromatic compounds. The synthesis of
the para-analogue of 7.2, a [3.3]paracyclophane (7.16), is currently being undertaken. In parallel
with this work, an attempt to prepare the [3.3](4,4’,4,4’)biphenylophane (7.17), the para-
analogue of 7.7, will also be attempted. It would be interesting to examine the synthetic
feasibility of these higher strained heteraphanes, as the preceding intramolecular cyclization
process that afforded these heteraphanes is anticipated to be more difficult. Also worthwhile is to
74
compare the structural and conformational features of 7.16 to 7.2 and 7.17 to 7.7 to examine the
effects of strain on the structural and conformational properties of these heteraphanes.
Figure 7-6. Structure of 7.16 and 7.17.
In the synthesis of 7.2, the linear polyverdazyl macromolecule 7.3 was formed as the
minor product (Scheme 7-1). It would be interesting to isolate the analogous linear polyverdazyl
macrostructure 7.18 in the synthesis of 7.7 (Figure 7-7) to determine how favourable this
competing polymerization process is compared to the formation of 7.3.
Figure 7-7. Structure of the polyverdazyl macrostructure 7.18.
In the synthesis of the biphenylophane 7.7, a low yield of 1-2 % yield was achieved. It
was proposed that the low yield was attributed to the formation of the semicarbazones 7.8 and
7.9, which were formed in 9-11 % and 4-6 % yield, respectively. In a side reaction, it was shown
that verdazyl radical 7.14 decomposed to form the semicarbazone 7.15 when left at room
temperature for more than seven days (Scheme 7-4). Based on this result, the reaction sequence
from 7.6 to 7.7 should be carried out for a minimum number of days to avoid decomposition of
7.6. To compensate for the loss of reaction time, the reaction could be heated to make the 1,3-DC
reactions more feasible.
The X-ray diffraction study of 7.7 revealed that the molecule was the (S,S)-stereoisomer
and it was proposed that a kinetic or thermodynamic control was in effect. It would be insightful
to employ DFT computations to determine if a kinetic control is in effect by calculating the
75
energy barriers to forming each of the stereoisomers – (R,R), (R,S), and (S,S) – from 7.6 and
from 7.12, or to determine if a thermodynamic control is in effect by calculating the relative
energies of the three stereoisomers.
7.6 References
(1) Yang, A.; Kasahara, T.; Chen, E. K. Y.; Hamer, G. K.; Georges, M. K. Eur. J. Org.
Chem. 2008, 4571-4574. (2) Chen, E. K. Y.; Bancerz, M.; Georges, M. K. Publication in Progress. (3) Lukkarila, J.; Hamer, G. K.; Georges, M. K. Publication in Progress. (4) Bodwell, G. J.; Li, J. Org. Lett. 2002, 4, 127-130. (b) Takemura, H.; Kariyazono, H.;
Kon, N.; Shinmyozu, T.; Inazu, T. J. Org. Chem. 1999, 64, 9077-9079. (c) Mitchell, R. H.; Weerawarna, K. S.; Bushnell, G. W. Tetrahedron Lett. 1984, 25, 907-910.
(5) (a) Nakamura, Y.; Mita, T.; Nishimura, J. Synlett 1995, 957-958. (b) Lai, Y.-H.; Ang, S.-G.; Wong, S.-Y. Tetrahedron Lett. 1997, 38, 2553-2556.
(6) Otwinowski, Z.; Minor, W. Methods in Enzymology: Macromolecular Crystallography
(Part A); (Eds.: C. W. Carter, R. M. Sweet); Academic Press: London, 1997; Vol. 276, pp 307-326.
(7) Blessing, R. H. Acta Crystallogr. 1995, A51, 33-38. (8) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112-122. (9) (a) Asakawa, M.; Ashton, P. R.; Menzer, S.; Raymo, F. M.; Stoddart, J. F.; White, A. J.
P.; Williams, D. J. Chem. Eur. J. 1996, 2, 877-893. (b) Ashton, P. R.; Menzer, S.; Raymo, F. M.; Shimizu, G. K. H.; Stoddart, J. F.; Williams, D. J. Chem. Commun. 1996, 487-490. (c) Raymo, F. M.; Stoddart, J. F. Pure. Appl. Chem. 1996, 68, 313-322.
76
8. Appendix
8.1 NMR Spectra for Structure 7.7
13C NMR spectrum obtained using a Bruker Avance III spectrometer at 296 K, operating at 100 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
77
COSY 1H NMR spectrum obtained using a Bruker Avance III spectrometer at 296 K, operating at 400 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR Solvent: CD2Cl2 with trace amount of C6D6)
78
1H NMR spectrum obtained using a Varian INOVA-500 spectrometer at 243 K, operating at 500 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
1H NMR spectrum obtained using a Varian INOVA-500 spectrometer at 253 K, operating at 500 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
79
1H NMR spectrum obtained using a Varian INOVA-500 spectrometer at 273 K, operating at 500 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
1H NMR spectrum obtained using a Varian INOVA-500 spectrometer at 293 K, operating at 500 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
80
1H NMR spectrum obtained using a Varian INOVA-500 spectrometer at 313 K, operating at 500 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
1H NMR spectrum obtained using a Varian INOVA-500 spectrometer at 323 K, operating at 500 MHz for [3.3](3,4’,3,4’)biphenylophane (7.7). (NMR solvent: CDCl3)
81
8.2 Single Crystal X-ray Diffraction Results for 7.7
Molecular structure of [3.3](3,4’,3,4’)biphenylophane (7.7) showing the atom labels. Bond lengths for [3.3](3,4’,3,4’)biphenylophane (7.7) as determined from single crystal X-ray analysis.
Bond Length (Å) Bond Length (Å)
O(1)-C(4) 1.213(2) C(9)-C(10) 1.382(3)
O(2)-C(22) 1.215(2) C(10)-C(11) 1.397(3)
N(1)-C(5) 1.417(2) C(11)-C(12) 1.398(3)
N(1)-N(2) 1.459(2) C(11)-C(13) 1.484(2)
N(1)-C(1) 1.528(2) C(13)-C(14) 1.392(3)
N(2)-C(4) 1.419(2) C(13)-C(18) 1.393(3)
N(2)-C(3) 1.467(2) C(14)-C(15) 1.385(3)
N(3)-C(4) 1.362(3) C(15)-C(16) 1.373(3)
N(3)-N(4) 1.393(2) C(16)-C(17) 1.398(3)
N(3)-C(6) 1.452(2) C(16)-C(19) 1.508(2)
N(4)-C(5) 1.282(2) C(17)-C(18) 1.389(2)
82
N(5)-C(23) 1.415(2) C(19)-C(20) 1.545(3)
N(5)-N(6) 1.452(2) C(20)-C(21) 1.526(3)
N(5)-C(19) 1.522(2) C(23)-C(25) 1.473(3)
N(6)-C(22) 1.406(2) C(25)-C(30) 1.393(3)
N(6)-C(21) 1.462(2) C(25)-C(26) 1.400(3)
N(7)-C(22) 1.359(3) C(26)-C(27) 1.371(3)
N(7)-N(8) 1.387(2) C(27)-C(28) 1.389(3)
N(7)-C(24) 1.453(2) C(28)-C(29) 1.383(3)
N(8)-C(23) 1.289(2) C(29)-C(30) 1.401(3)
C(1)-C(34) 1.502(2) C(29)-C(31) 1.485(3)
C(1)-C(2) 1.539(3) C(31)-C(32) 1.396(3)
C(2)-C(3) 1.521(3) C(31)-C(36) 1.399(3)
C(5)-C(7) 1.474(3) C(32)-C(33) 1.389(3)
C(7)-C(8) 1.389(3) C(33)-C(34) 1.384(3)
C(7)-C(12) 1.395(2) C(34)-C(35) 1.402(3)
C(8)-C(9) 1.368(3) C(35)-C(36) 1.381(3) *Estimated standard deviations in parentheses.
Bond angles for [3.3](3,4’,3,4’)biphenylophane (7.7) as determined from single crystal X-ray analysis.
Bond Bond Angle (Degrees) Bond Bond Angle (Degrees)
C(5)-N(1)-N(2) 111.60(14) C(14)-C(13)-C(18) 117.63(17)
C(5)-N(1)-C(1) 116.60(16) C(14)-C(13)-C(11) 120.54(17)
N(2)-N(1)-C(1) 107.81(13) C(18)-C(13)-C(11) 121.83(17)
C(4)-N(2)-N(1) 116.85(16) C(15)-C(14)-C(13) 121.30(18)
C(4)-N(2)-C(3) 115.00(15) C(16)-C(15)-C(14) 121.18(18)
N(1)-N(2)-C(3) 102.41(14) C(15)-C(16)-C(17) 118.27(17)
83
C(4)-N(3)-N(4) 124.13(16) C(15)-C(16)-C(19) 120.57(18)
C(4)-N(3)-C(6) 121.00(18) C(17)-C(16)-C(19) 121.16(18)
N(4)-N(3)-C(6) 114.41(17) C(18)-C(17)-C(16) 120.74(18)
C(5)-N(4)-N(3) 117.06(16) C(17)-C(18)-C(13) 120.87(18)
C(23)-N(5)-N(6) 110.95(14) C(16)-C(19)-N(5) 110.66(14)
C(23)-N(5)-C(19) 116.87(16) C(16)-C(19)-C(20) 114.79(16)
N(6)-N(5)-C(19) 107.55(13) N(5)-C(19)-C(20) 102.24(15)
C(22)-N(6)-N(5) 116.35(17) C(21)-C(20)-C(19) 104.98(15)
C(22)-N(6)-C(21) 114.71(15) N(6)-C(21)-C(20) 102.78(17)
N(5)-N(6)-C(21) 102.70(13) O(2)-C(22)-N(7) 123.27(19)
C(22)-N(7)-N(8) 123.17(16) O(2)-C(22)-N(6) 121.90(2)
C(22)-N(7)-C(24) 119.45(17) N(7)-C(22)-N(6) 114.69(17)
N(8)-N(7)-C(24) 114.26(17) N(8)-C(23)-N(5) 123.44(17)
C(23)-N(8)-N(7) 116.69(16) N(8)-C(23)-C(25) 117.49(17)
C(34)-C(1)-N(1) 110.76(14) N(5)-C(23)-C(25) 119.00(16)
C(34)-C(1)-C(2) 113.69(15) C(30)-C(25)-C(26) 119.16(18)
N(1)-C(1)-C(2) 102.46(16) C(30)-C(25)-C(23) 121.73(18)
C(3)-C(2)-C(1) 105.27(15) C(26)-C(25)-C(23) 119.11(17)
N(2)-C(3)-C(2) 103.83(17) C(27)-C(26)-C(25) 119.89(19)
O(1)-C(4)-N(3) 124.16(19) C(26)-C(27)-C(28) 120.50(2)
O(1)-C(4)-N(2) 122.10(2) C(29)-C(28)-C(27) 120.94(19)
N(3)-C(4)-N(2) 113.56(17) C(28)-C(29)-C(30) 118.37(18)
N(4)-C(5)-N(1) 123.38(17) C(28)-C(29)-C(31) 120.28(17)
N(4)-C(5)-C(7) 117.67(17) C(30)-C(29)-C(31) 121.33(17)
N(1)-C(5)-C(7) 118.95(15) C(25)-C(30)-C(29) 120.99(18)
C(8)-C(7)-C(12) 118.61(18) C(32)-C(31)-C(36) 117.23(17)
84
C(8)-C(7)-C(5) 118.50(16) C(32)-C(31)-C(29) 119.94(19)
C(12)-C(7)-C(5) 122.88(17) C(36)-C(31)-C(29) 122.82(17)
C(9)-C(8)-C(7) 120.87(18) C(33)-C(32)-C(31) 121.58(19)
C(8)-C(9)-C(10) 120.50(19) C(34)-C(33)-C(32) 120.92(18)
C(9)-C(10)-C(11) 120.49(19) C(33)-C(34)-C(35) 117.90(17)
C(10)-C(11)-C(12) 118.26(17) C(33)-C(34)-C(1) 120.78(17)
C(10)-C(11)-C(13) 120.59(17) C(35)-C(34)-C(1) 121.32(19)
C(12)-C(11)-C(13) 121.14(16) C(36)-C(35)-C(34) 121.20(2)
C(7)-C(12)-C(11) 121.21(17) C(35)-C(36)-C(31) 121.18(18) *Estimated standard deviations in parentheses.